U.S. patent application number 12/307512 was filed with the patent office on 2009-12-17 for benzimidazole cannabinoid agonists bearing a substituted heterocyclic group.
This patent application is currently assigned to JANSSEN PHARMACEUTICA NV. Invention is credited to Michel Anna Jozef De Cleyn, Henricus Jacobus Maria Gijsen, Michel Surkyn, Bie Maria Pieter Verbist.
Application Number | 20090312339 12/307512 |
Document ID | / |
Family ID | 37453123 |
Filed Date | 2009-12-17 |
United States Patent
Application |
20090312339 |
Kind Code |
A1 |
Gijsen; Henricus Jacobus Maria ;
et al. |
December 17, 2009 |
BENZIMIDAZOLE CANNABINOID AGONISTS BEARING A SUBSTITUTED
HETEROCYCLIC GROUP
Abstract
The present invention is related to novel benzimidazole
compounds of formula (I) having cannabinoid receptor agonistic
properties, pharmaceutical compositions comprising these compounds,
chemical processes for preparing these compounds and their use in
the treatment of diseases linked to the mediation of the
cannabinoid receptors in animals, in particular humans.
##STR00001##
Inventors: |
Gijsen; Henricus Jacobus Maria;
(Beerse, BE) ; De Cleyn; Michel Anna Jozef;
(Beerse, BE) ; Surkyn; Michel; (Beerse, BE)
; Verbist; Bie Maria Pieter; (Beerse, BE) |
Correspondence
Address: |
PHILIP S. JOHNSON;JOHNSON & JOHNSON
ONE JOHNSON & JOHNSON PLAZA
NEW BRUNSWICK
NJ
08933-7003
US
|
Assignee: |
JANSSEN PHARMACEUTICA NV
Beerse
BE
|
Family ID: |
37453123 |
Appl. No.: |
12/307512 |
Filed: |
July 2, 2007 |
PCT Filed: |
July 2, 2007 |
PCT NO: |
PCT/EP2007/056619 |
371 Date: |
January 5, 2009 |
Current U.S.
Class: |
514/252.06 ;
514/338; 544/238; 546/273.4 |
Current CPC
Class: |
A61P 11/06 20180101;
A61P 35/00 20180101; A61P 13/10 20180101; A61P 25/04 20180101; C07D
417/12 20130101; A61P 9/10 20180101; C07D 401/12 20130101; A61P
11/00 20180101; A61P 25/00 20180101; A61P 37/08 20180101; A61P 1/16
20180101; A61P 19/08 20180101; A61P 19/10 20180101; A61P 17/06
20180101; A61P 37/02 20180101; C07D 405/14 20130101; A61P 1/08
20180101; A61P 21/00 20180101; A61P 29/00 20180101; A61P 25/02
20180101; A61P 25/08 20180101; A61P 37/06 20180101; A61P 9/12
20180101; C07D 413/14 20130101; A61P 9/00 20180101; C07D 403/12
20130101; C07D 409/14 20130101; A61P 1/04 20180101 |
Class at
Publication: |
514/252.06 ;
546/273.4; 514/338; 544/238 |
International
Class: |
A61K 31/501 20060101
A61K031/501; C07D 407/14 20060101 C07D407/14; A61K 31/4439 20060101
A61K031/4439; C07D 403/02 20060101 C07D403/02 |
Foreign Application Data
Date |
Code |
Application Number |
Jul 4, 2006 |
EP |
06116564.3 |
Claims
1. Compound of formula (I) ##STR00393## the pharmaceutically
acceptable acid addition salts and the stereochemically isomeric
forms thereof, wherein n is an integer 1 or 2; R.sup.1 is
C.sub.2-6alkyl; C.sub.1-6alkyl substituted with 1, 2 or 3
substituents each independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.1-4alkyloxy, cyano, nitro, amino, and mono-
or di(C.sub.1-4alkyl)amino; C.sub.1-6alkyl substituted with a
cyclic group selected from C.sub.3-8cycloalkyl,
oxoC.sub.3-8cycloalkyl, C.sub.5-8cycloalkenyl,
bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl and
bicyclo[3.1.1]heptanyl, wherein said cyclic group is optionally
substituted with one or more substituents each independently
selected from halo, hydroxy, C.sub.1-4alkyl, C.sub.1-4alkyloxy,
cyano, nitro, NR.sup.5R.sup.6 or CONR.sup.5R.sup.6 wherein R.sup.5
and R.sup.6 are independently selected from hydrogen or
C.sub.1-14alkyl; or C.sub.1-6alkyl substituted with a heterocycle
selected from pyrrolidinyl, piperidinyl, homopiperidinyl,
piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,
1,1-dioxo-tetrahydro-thiopyranyl, [1,3]dioxolanyl, [1,4]dioxolanyl,
[1,3]dioxanyl, 5-oxo-pyrrolidin-2-yl, or 2-oxo-oxepanyl; wherein
said heterocycle is optionally substituted with one or two
substituents each independently selected from C.sub.1-14alkyl,
polyhaloC.sub.1-4alkyl, halo, hydroxy, C.sub.1-4alkyloxy, cyano,
trifluoromethyl, COR.sup.5, COOR.sup.5, CONR.sup.5R.sup.6,
SO.sub.2R.sup.5 wherein R.sup.5 and R.sup.6 are independently
selected from hydrogen or C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl;
R.sup.2 is C.sub.2-6alkyl; C.sub.1-6alkyl substituted with 1, 2 or
3 substituents each independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkyloxy,
polyhaloC.sub.1-4alkyloxy, trifluoromethyl, cyano, nitro,
NR.sup.7R.sup.8, CONR.sup.7R.sup.8, or NHCOR.sup.7 wherein R.sup.7
and R.sup.8 are independently selected from hydrogen,
C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl; C.sub.3-6alkenyl;
C.sub.3-6alkynyl; C.sub.3-6cycloalkyl; or cyclic group selected
from pyrrolidininyl, piperidinyl, piperazinyl, morpholinyl,
tetrahydrofuranyl, tetrahydropyranyl, [1,3]dioxolanyl,
[1,3]dioxanyl, [1,4]dioxanyl, 5-oxo-pyrrolidin-2-yl,
bicyclo[2.2.1]hept-2-enyl, and bicyclo[3.1. 1]heptanyl; wherein
said cyclic group is optionally substituted with one or two
substituents each independently selected from C.sub.1-4alkyl, halo,
hydroxy, C.sub.1-4alkyloxy, or trifluoromethyl; R.sup.3 is
hydrogen, halo, C.sub.1-4alkyl, C.sub.1-4alkyloxy, trifluoromethyl
or cyano; R.sup.4 is heteroaryl; heteroaryl is selected from
N-oxy-pyridinyl, N-oxy-pyridazinyl, N-oxy-pyrimidinyl or
N-oxy-pyrazinyl; or selected from furanyl, thiophenyl, pyrrolyl,
pyrazolyl, imidazolyl, isoxazolyl, thiazolyl, triazolyl,
tetrazolyl, isothiazolyl, thiadiazolyl, oxadiazolyl, pyridinyl,
pyridazinyl, pyrimidinyl, pyrazinyl, triazinyl, N-oxy-pyridinyl,
N-oxy-pyridazinyl, N-oxy-pyrimidinyl, N-oxy-pyrazinyl or
2-oxo-1,2-dihydro-pyridinyl, each substituted with 1, 2 or 3
substituents each independently selected from halo; hydroxy;
C.sub.1-4alkyl; C.sub.3-6cycloalkyl; C.sub.2-6alkenyl;
C.sub.2-6alkenyl substituted with 1 or 2 substituents selected from
halo; C.sub.2-6alkynyl; C.sub.2-6alkynyl substituted with
C.sub.1-4alkyloxy; C.sub.1-4alkyloxy;
C.sub.1-4alkyloxyC.sub.1-4alkyl; polyhaloC.sub.1-4alkyl;
polyhaloC.sub.1-4alkyloxy; cyano; nitro; NR.sup.9R.sup.10;
R.sup.11-carbonyl; R.sup.11--SO.sub.2--; C.sub.1-4alkyl substituted
with hydroxy, NR.sup.9R.sup.10, R.sup.11-carbonyl or
R.sup.11--SO.sub.2--; oxadiazolyl optionally substituted with
C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl or C.sub.3-6cycloalkyl; or
dioxolanyl optionally substituted with 1 or 2 C.sub.1-4alkyl;
C.sub.1-4alkyloxy substituted with hydroxy, C.sub.1-4alkyloxy,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkyloxycarbonylamino, amino,
di(C.sub.1-4alkyl)amino or morpholinyl;
C.sub.1-4alkylcarbonylaminoC.sub.1-4alkylamino;
C.sub.1-4alkyloxyC.sub.1-4alkylamino; wherein R.sup.9 and R.sup.10
are independently from another selected from hydrogen,
C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl, aminosulfonyl, or
C.sub.1-8alkylsulfonyl; or R.sup.11-carbonyl; wherein R.sup.9 and
R.sup.10 are taken together with the nitrogen atom bearing R.sup.9
and R.sup.10 may form a pyrrolidinyl, piperidinyl, piperazinyl or
morpholinyl ring; and wherein R.sup.11 is C.sub.1-4alkyl,
C.sub.1-4alkyloxy, hydroxy, amino, mono- or
di-(C.sub.1-4alkyl)amino, (hydroxyC.sub.1-4alkyl)amino,
(C.sub.1-4alkyloxyC.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, pyrrolidinyl, piperidinyl,
morpholinyl, N-methyl-piperazinyl, or C.sub.1-4alkyl substituted
with hydroxy, C.sub.1-4alkyloxy, trifluoromethyl,
C.sub.1-4alkyloxyC.sub.1-4alkyl, pyrrolidinyl, piperidinyl,
morpholinyl, N-methyl-piperazinyl, or 2-oxo-imidazolidin-1-yl.
2. A compound as claimed in claim 1 wherein n is 2.
3. A compound as claimed in claim 1 wherein R.sup.1 is
C.sub.1-6alkyl substituted with a cyclic group selected from
C.sub.3-8cycloalkyl or tetrahydropyranyl.
4. A compound as claimed in claim 1 wherein R.sup.2 is
C.sub.1-6alkyl.
5. A compound as claimed in claim 1 wherein R.sup.4 is
N-oxy-pyridinyl.
6. A compound as claimed claim 1 wherein R.sup.4 is R.sup.4 is
furanyl, thiophenyl, oxadiazolyl, pyridinyl, or pyridazinyl; each
substituted with 1, 2 or 3 substituents each independently selected
from halo; hydroxy; C.sub.1-4alkyl; C.sub.1-4alkyloxy;
polyhaloC.sub.1-4alkyl; polyhaloC.sub.1-4alkyloxy; cyano;
NR.sup.9R.sup.10; R.sup.11-carbonyl; R.sup.11--SO.sub.2--; or
oxadiazolyl optionally substituted with C.sub.1-4alkyl; wherein
R.sup.9 and R.sup.10 are independently from another selected from
hydrogen or R.sup.11-carbonyl; and wherein R.sup.11 is
C.sub.1-4alkyl, amino, or morpholinyl.
7. A pharmaceutical composition comprising a pharmaceutically
acceptable carrier and a therapeutically active amount of a
compound as claimed in claim 1.
8. A process for preparing a pharmaceutical composition as claimed
in claim 7 wherein a therapeutically active amount of a compound as
claimed in claim 1 is intimately mixed with a pharmaceutically
acceptable carrier.
9. A compound as claimed in claim 1 for use as a medicine.
10. A compound as claimed in claim 1 for the manufacture of a
medicament for the treatment of a condition or a disease mediated
by cannabiniod receptor 2 activity, in particular CB2 agonistic
activity.
11. A process for preparing a compound of formula (I-a), defined as
a compound of formula (I) as claimed in claim 1 wherein n is 1, by
S-oxidizing an intermediate (A), wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are as defined in claim 1, with an oxidizing agent such
as, NaIO.sub.4, tert-butyloxychloride, acyl nitrites, sodium
perborate and peracids such as meta-chloroperbenzoic acid.
##STR00394##
12. A process for preparing a compound of formula (I-b), defined as
a compound of formula (I) as claimed in claim 1 wherein n is 2, by
S-oxidizing an intermediate (A), wherein R.sup.1, R.sup.2, R.sup.3
and R.sup.4 are as defined in claim 1, with an oxidizing agent such
as, NaIO.sub.4, tert-butyloxychloride, acyl nitrites, sodium
perborate and peracids such as meta-chloroperbenzoic acid.
##STR00395##
13. A process for preparing a compound of formula (I-b), defined as
a compound of formula (I) as claimed in claim 1 wherein n is 2, by
subjecting an intermediate of formula (XIII), wherein R.sup.1,
R.sup.2, R.sup.3 and R.sup.4 are as defined in claim 1, to a
condensation reaction under acidic or basic conditions.
##STR00396##
Description
[0001] The present invention is related to novel benzimidazole
compounds of formula (I) having selective cannabinoid receptor 2
agonistic properties, pharmaceutical compositions comprising these
compounds, chemical processes for preparing these compounds and
their use in the treatment of diseases linked to the mediation of
the cannabinoid receptors in animals, in particular humans.
[0002] Classical cannabinoids such as the marijuana derived
cannabinoid .DELTA..sup.9-tetrahydro-cannabinol,
(.DELTA..sup.9-THC) produce their pharmacological effects via
interaction with specific cannabinoid receptors in the body. So
far, two cannabinoid receptors have been characterized: CB1, a
receptor found in the mammalian brain and peripheral tissues and
CB2, a receptor found predominantly in the peripheral tissues.
Compounds that are agonists or antagonists for one or both of these
receptors have been shown to provide a variety of pharmacological
effects. There is considerable interest in developing cannabinoid
analogs that have selective CB2 agonistic activity since it is
believed high selectivity for CB2 receptor may offer avenues for
harnessing the beneficial effect of CB receptor agonists while
avoiding the central adverse events seen with cannabinoid
structures (see e.g. Expert Opinion on Investigational Drugs
(2005), 14(6), 695-703).
[0003] WO-2006/048754 discloses sulfonyl benzimidazole derivatives
having CB2 agonistic activity.
[0004] The compounds of the present invention differ structurally
from the cited art known compounds by the presence of a
heterocyclic moiety on the sulfonyl group which is always
substituted.
[0005] It was found the compounds of the present invention
unexpectedly have a higher ratio of CB2 agonism over CB1 agonism
than the cited art known compounds. Hence the compounds of the
present invention are more selective CB2 agonists than the art
known compounds from WO-2006/048754.
[0006] The present invention relates to novel compounds of formula
(I)
##STR00002##
the pharmaceutically acceptable acid addition salts and the
stereochemically isomeric forms thereof, wherein [0007] n is an
integer 1 or 2; [0008] R.sup.1 is C.sub.2-6alkyl; [0009]
C.sub.1-6alkyl substituted with 1, 2 or 3 substituents each
independently selected from halo, hydroxy, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, cyano, nitro, amino, and mono- or
di(C.sub.1-4alkyl)amino; [0010] C.sub.1-6alkyl substituted with a
cyclic group selected from C.sub.3-8cycloalkyl,
oxoC.sub.3-8cycloalkyl, C.sub.5-8cycloalkenyl,
bicyclo[2.2.1]hept-2-enyl, bicyclo[2.2.2]octanyl and
bicyclo[3.1.1]heptanyl, wherein said cyclic group is optionally
substituted with one or more substituents each independently
selected from halo, hydroxy, C.sub.1-4alkyl, C.sub.1-4alkyloxy,
cyano, nitro, NR.sup.5R.sup.6 or CONR.sup.5R.sup.6 wherein R.sup.5
and R.sup.6 are independently selected from hydrogen or
C.sub.1-4alkyl; or [0011] C.sub.1-6alkyl substituted with a
heterocycle selected from pyrrolidinyl, piperidinyl,
homopiperidinyl, piperazinyl, morpholinyl, tetrahydrofuranyl,
tetrahydropyranyl, 1,1-dioxo-tetrahydrothiopyranyl,
[1,3]dioxolanyl, [1,4]dioxolanyl, [1,3]dioxanyl,
5-oxo-pyrrolidin-2-yl, or 2-oxo-oxepanyl; wherein said heterocycle
is optionally substituted with one or two substituents each
independently selected from C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl,
halo, hydroxy, C.sub.1-4alkyloxy, cyano, trifluoromethyl,
COR.sup.5, COOR.sup.5, CONR.sup.5R.sup.6, SO.sub.2R.sup.5 wherein
R.sup.5 and R.sup.6 are independently selected from hydrogen or
C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl; [0012] R.sup.2 is
C.sub.2-6alkyl; [0013] C.sub.1-6alkyl substituted with 1, 2 or 3
substituents each independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkyloxy,
polyhaloC.sub.1-4alkyloxy, trifluoromethyl, cyano, nitro,
NR.sup.7R.sup.8, CONR.sup.7R.sup.8, or NHCOR.sup.7 wherein R.sup.7
and R.sup.8 are independently selected from hydrogen,
C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl; [0014] C.sub.3-6alkenyl;
[0015] C.sub.3-6alkynyl; [0016] C.sub.3-6cycloalkyl; or [0017]
cyclic group selected from pyrrolidininyl, piperidinyl,
piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,
[1,3]dioxolanyl, [1,3]dioxanyl, [1,4]dioxanyl,
5-oxo-pyrrolidin-2-yl, bicyclo[2.2.1]hept-2-enyl, and
bicyclo[3.1.1]heptanyl; wherein said cyclic group is optionally
substituted with one or two substituents each independently
selected from C.sub.1-4alkyl, halo, hydroxy, C.sub.1-4alkyloxy, or
trifluoromethyl; [0018] R.sup.3 is hydrogen, halo, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, trifluoromethyl or cyano; [0019] R.sup.4 is
heteroaryl; [0020] heteroaryl is selected from N-oxy-pyridinyl,
N-oxy-pyridazinyl, N-oxy-pyrimidinyl or N-oxy-pyrazinyl; or [0021]
selected from furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl,
isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, N-oxy-pyridinyl, N-oxy-pyridazinyl,
N-oxy-pyrimidinyl, N-oxy-pyrazinyl or 2-oxo-1,2-dihydro-pyridinyl,
each substituted with 1, 2 or 3 substituents each independently
selected from halo; hydroxy; C.sub.1-4alkyl; C.sub.3-6cycloalkyl;
C.sub.2-6alkenyl; C.sub.2-6alkenyl substituted with 1 or 2
substituents selected from halo; C.sub.2-6alkynyl; C.sub.2-6alkynyl
substituted with C.sub.1-4alkyloxy; C.sub.1-4alkyloxy;
C.sub.1-4alkyloxyC.sub.1-4alkyl; polyhaloC.sub.1-4alkyl;
polyhaloC.sub.1-4alkyloxy; cyano; nitro; NR.sup.9R.sup.10;
R.sup.11-carbonyl; R.sup.11--SO.sub.2--; C.sub.1-4alkyl substituted
with hydroxy, NR.sup.9R.sup.10, R.sup.11-carbonyl or
R.sup.11--SO.sub.2--; oxadiazolyl optionally substituted with
C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl or C.sub.3-6cycloalkyl;
dioxolanyl optionally substituted with 1 or 2 C.sub.1-4alkyl;
C.sub.1-4alkyloxy substituted with hydroxy, C.sub.1-4alkyloxy,
C.sub.1-4alkylcarbonylamino, C.sub.1-4alkyloxycarbonylamino, amino,
di(C.sub.1-4alkyl)amino or morpholinyl;
C.sub.1-4alkylcarbonylaminoC.sub.1-4alkylamino;
C.sub.1-4alkyloxyC.sub.1-4alkylamino; [0022] wherein R.sup.9 and
R.sup.10 are independently from another selected from hydrogen,
C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl, aminosulfonyl, or
C.sub.1-8alkylsulfonyl; or R.sup.11-carbonyl; [0023] wherein
R.sup.9 and R.sup.10 are taken together with the nitrogen atom
bearing R.sup.9 and R.sup.10 may form a pyrrolidinyl, piperidinyl,
piperazinyl or morpholinyl ring; and [0024] wherein R.sup.11 is
C.sub.1-4alkyl, C.sub.1-4alkyloxy, hydroxy, amino, mono- or
di-(C.sub.1-4alkyl)amino, (hydroxyC.sub.1-4alkyl)amino,
(C.sub.1-4alkyloxyC.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, pyrrolidinyl, piperidinyl,
morpholinyl, N-methyl-piperazinyl, or C.sub.1-4alkyl substituted
with hydroxy, C.sub.1-4alkyloxy, trifluoromethyl,
C.sub.1-4alkyloxyC.sub.1-4alkyl, pyrrolidinyl, piperidinyl,
morpholinyl, N-methyl-piperazinyl, or 2-oxo-imidazolidin-1-yl.
[0025] As used in the foregoing definitions: [0026] halo is generic
to fluoro, chloro, bromo and iodo; [0027] C.sub.1-4alkyl defines
straight and branched chain saturated hydrocarbon radicals having
from 1 to 4 carbon atoms such as, for example, methyl, ethyl,
propyl, butyl, 1-methyl-ethyl, 2-methylpropyl and the like; [0028]
C.sub.1-6alkyl is meant to include C.sub.1-4alkyl and the higher
homologues thereof having 5 or 6 carbon atoms, such as, for
example, 2-methylbutyl, pentyl, hexyl and the like; [0029]
C.sub.2-6alkyl defines straight and branched chain saturated
hydrocarbon radicals having from 2 to 6 carbon atoms such as, for
example, ethyl, propyl, butyl, 1-methylethyl, 2-methylpropyl
2-methylbutyl, pentyl, hexyl and the like; [0030] C.sub.1-8alkyl is
meant to include C.sub.1-6alkyl and the higher homologues thereof
having 7 to 8 carbon atoms, such as for instance heptyl,
ethylhexyl, octyl, and the like; [0031] polyhaloC.sub.1-4alkyl is
defined as polyhalosubstituted C.sub.1-4alkyl, in particular
C.sub.1-4alkyl (as hereinabove defined) substituted with 2 to 6
halogen atoms such as difluoromethyl, trifluoromethyl,
trifluoroethyl, and the like; [0032] C.sub.2-6alkenyl defines
straight and branched chain hydrocarbon radicals containing one
double bond and having from 2 to 6 carbon atoms such as, for
example, ethenyl, 2-propenyl, 3-butenyl, 2-butenyl, 2-pentenyl,
3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl, 2-hexenyl and the like;
[0033] C.sub.3-6alkenyl defines straight and branched chain
hydrocarbon radicals containing one double bond and having from 3
to 6 carbon atoms such as, for example, 2-propenyl, 3-butenyl,
2-butenyl, 2-pentenyl, 3-pentenyl, 3-methyl-2-butenyl, 3-hexenyl,
2-hexenyl and the like; [0034] C.sub.2-6alkynyl defines straight
and branched chain hydrocarbon radicals containing one triple bond
and having from 2 to 6 carbon atoms such as, for example, ethynyl,
2-propynyl, 3-butynyl, 2-butynyl, 2-pentynyl, 3-pentynyl,
3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl and the like; [0035]
C.sub.3-6alkynyl defines straight and branched chain hydrocarbon
radicals containing one triple bond and having from 3 to 6 carbon
atoms such as, for example, 2-propynyl, 3-butynyl, 2-butynyl,
2-pentynyl, 3-pentynyl, 3-methyl-2-butynyl, 3-hexynyl, 2-hexynyl
and the like; [0036] C.sub.3-6cycloalkyl is generic to cyclopropyl,
cyclobutyl, cyclopentyl, and cyclohexyl; [0037] C.sub.3-8cycloalkyl
is generic to cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl,
cycloheptyl and cyclooctyl; [0038] C.sub.6-8cycloalkyl is generic
to cyclohexyl, cycloheptyl and cyclooctyl; [0039]
C.sub.5-8cycloalkenyl is generic to cyclopentenyl, cyclohexenyl,
cycloheptenyl and cyclooctenyl.
[0040] The pharmaceutically acceptable acid addition salts as
mentioned hereinabove are meant to comprise the therapeutically
active non-toxic acid addition salt forms which the compounds of
formula (I) are able to form. These pharmaceutically acceptable
acid addition salts can conveniently be obtained by treating the
base form with such appropriate acid. Appropriate acids comprise,
for example, inorganic acids such as hydrohalic acids, e.g.
hydrochloric or hydrobromic acid, sulfuric, nitric, phosphoric and
the like acids; or organic acids such as, for example, acetic,
propanoic, hydroxyacetic, lactic, pyruvic, oxalic (i.e.
ethanedioic), malonic, succinic (i.e. butanedioic acid), maleic,
fumaric, malic, tartaric, citric, methanesulfonic, ethanesulfonic,
benzenesulfonic, p-toluenesulfonic, cyclamic, salicylic,
p-aminosalicylic, pamoic and the like acids.
[0041] Conversely said salt forms can be converted by treatment
with an appropriate base into the free base form.
[0042] The compounds of formula (I) may exist in both unsolvated
and solvated forms. The term `solvate` is used herein to describe a
molecular complex comprising a compound of the invention and one or
more pharmaceutically acceptable solvent molecules, e.g. ethanol.
The term `hydrate` is used when said solvent is water.
[0043] The term "stereochemically isomeric forms" as used
hereinbefore defines all the possible isomeric forms which the
compounds of formula (I) may possess. Unless otherwise mentioned or
indicated, the chemical designation of compounds denotes the
mixture of all possible stereochemically isomeric forms, said
mixtures containing all diastereomers and enantiomers of the basic
molecular structure. More in particular, stereogenic centers may
have the R- or S-configuration; substituents on bivalent cyclic
(partially) saturated radicals may have either the cis- or
trans-configuration. Compounds encompassing double bonds can have
an E or Z-stereochemistry at said double bond. Stereochemically
isomeric forms of the compounds of formula (I) are obviously
intended to be embraced within the scope of this invention.
[0044] The absolute stereochemical configuration of the compounds
of formula (I) and of the intermediates used in their preparation
may easily be determined by those skilled in the art while using
well-known methods such as, for example, X-ray diffraction.
[0045] Some of the compounds of formula (I) may also exist in their
tautomeric form. Such forms although not explicitly indicated in
the above formula are intended to be included within the scope of
the present invention. For instance, when an aromatic heterocyclic
ring is substituted with hydroxy, the keto-form may be the mainly
populated tautomer.
[0046] In the framework of this application, with the expression "a
compound according to the invention" it is also meant to include a
compound according to the general formula (I) and a pro-drug
thereof, or a isotopically labelled compound thereof.
[0047] Also within the scope of the invention are so-called
"pro-drugs" of the compounds of formula (I). Pro-drugs are certain
derivatives of pharmaceutically active compounds which may have
little or no pharmacological activity themselves which can, when
administered into or onto the body, be converted into compounds of
formula (I) having the desired pharmaceutical activity, e.g. by
hydrolytic cleavage. Such derivatives are referred to as
"pro-drugs".
[0048] In an embodiment, the present invention relates to compounds
of formula (I) wherein wherein [0049] n is an integer 1 or 2;
[0050] R.sup.1 is C.sub.2-6alkyl; [0051] C.sub.1-6alkyl substituted
with 1, 2 or 3 substituents each independently selected from halo,
hydroxy, C.sub.1-4alkyl, C.sub.1-4alkyloxy, cyano, nitro, amino,
and mono- or di(C.sub.1-4alkyl)amino; [0052] C.sub.1-6alkyl
substituted with a cyclic group selected from C.sub.3-8cycloalkyl,
C.sub.5-8cycloalkenyl, bicyclo[2.2.1]hept-2-enyl,
bicyclo[2.2.2]octanyl and bicyclo[3.1.1]heptanyl, wherein said
cyclic group is optionally substituted with one or more
substituents each independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.1-4alkyloxy, cyano, nitro, NR.sup.5R.sup.6 or
CONR.sup.5R.sup.6 wherein R.sup.5 and R.sup.6 are independently
selected from hydrogen or C.sub.1-4alkyl; or [0053] C.sub.1-6alkyl
substituted with a heterocycle selected from pyrrolidinyl,
piperidinyl, homopiperidinyl, piperazinyl, morpholinyl,
tetrahydrofuranyl, tetrahydropyranyl,
1,1-dioxo-tetrahydrothiopyranyl, [1,3]dioxolanyl, [1,4]dioxolanyl,
[1,3]dioxanyl, 5-oxo-pyrrolidin-2-yl; wherein said heterocycle is
optionally substituted with one or two substituents each
independently selected from C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl,
halo, hydroxy, C.sub.1-4alkyloxy, cyano, trifluoromethyl,
COR.sup.5, COOR.sup.5, CONR.sup.5R.sup.6, SO.sub.2R.sup.5 wherein
R.sup.5 and R.sup.6 are independently selected from hydrogen or
C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl; [0054] R.sup.2 is
C.sub.2-6alkyl; [0055] C.sub.1-6alkyl substituted with 1, 2 or 3
substituents each independently selected from halo, hydroxy,
C.sub.1-4alkyl, C.sub.3-6cycloalkyl, C.sub.1-4alkyloxy,
polyhaloC.sub.1-4alkyloxy, trifluoromethyl, cyano, nitro,
NR.sup.7R.sup.8, CONR.sup.7R.sup.8, or NHCOR.sup.7 wherein R.sup.7
and R.sup.8 are independently selected from hydrogen,
C.sub.1-4alkyl or polyhaloC.sub.1-4alkyl; [0056] C.sub.3-6alkenyl;
[0057] C.sub.3-6alkynyl; [0058] C.sub.3-6cycloalkyl; or [0059]
cyclic group selected from pyrrolidininyl, piperidinyl,
piperazinyl, morpholinyl, tetrahydrofuranyl, tetrahydropyranyl,
[1,3]dioxolanyl, [1,3]dioxanyl, [1,4]dioxanyl,
5-oxo-pyrrolidin-2-yl, bicyclo[2.2.1]hept-2-enyl, and
bicyclo[3.1.1]heptanyl; wherein said cyclic group is optionally
substituted with one or two substituents each independently
selected from C.sub.1-4alkyl, halo, hydroxy, C.sub.1-4alkyloxy, or
trifluoromethyl; [0060] R.sup.3 is hydrogen, halo, C.sub.1-4alkyl,
C.sub.1-4alkyloxy, trifluoromethyl or cyano; [0061] R.sup.4 is
heteroaryl; [0062] heteroaryl is selected from N-oxy-pyridinyl,
N-oxy-pyridazinyl, N-oxy-pyrimidinyl or N-oxy-pyrazinyl; or [0063]
selected from furanyl, thiophenyl, pyrrolyl, pyrazolyl, imidazolyl,
isoxazolyl, thiazolyl, triazolyl, tetrazolyl, isothiazolyl,
thiadiazolyl, oxadiazolyl, pyridinyl, pyridazinyl, pyrimidinyl,
pyrazinyl, triazinyl, N-oxy-pyridinyl, N-oxy-pyridazinyl,
N-oxy-pyrimidinyl or N-oxy-pyrazinyl, each substituted with 1, 2 or
3 substituents each independently selected from halo; hydroxy;
C.sub.1-4alkyl; C.sub.3-6cycloalkyl; C.sub.2-6alkenyl;
C.sub.2-6alkynyl; C.sub.1-4alkyloxy;
C.sub.1-4alkyloxyC.sub.1-4alkyl; polyhaloC.sub.1-4alkyl;
polyhaloC.sub.1-4alkyloxy; cyano; nitro; NR.sup.9R.sup.10;
R.sup.11-carbonyl; R.sup.11--SO.sub.2--; C.sub.1-4alkyl substituted
with hydroxy, NR.sup.9R.sup.10, R.sup.11-carbonyl or
R.sup.11--SO.sub.2--; oxadiazolyl optionally substituted with
C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl or C.sub.3-6cycloalkyl; or
dioxolanyl optionally substituted with 1 or 2 C.sub.1-4alkyl;
[0064] wherein R.sup.9 and R.sup.10 are independently from another
selected from hydrogen, C.sub.1-4alkyl, polyhaloC.sub.1-4alkyl,
aminosulfonyl, or C.sub.1-8alkylsulfonyl; or R.sup.11-carbonyl;
[0065] wherein R.sup.9 and R.sup.10. are taken together with the
nitrogen atom bearing R.sup.9 and R.sup.10 may form a pyrrolidinyl,
piperidinyl, piperazinyl or morpholinyl ring; and [0066] wherein
R.sup.11 is C.sub.1-4alkyl, hydroxy, amino, mono- or
di-(C.sub.1-4alkyl)amino, (hydroxyC.sub.1-4alkyl)amino,
(C.sub.1-4alkyloxyC.sub.1-4alkyl)amino,
di(C.sub.1-4alkyl)aminoC.sub.1-4alkyl, pyrrolidinyl, piperidinyl,
morpholinyl, N-methyl-piperazinyl, or C.sub.1-4alkyl substituted
with hydroxy, C.sub.1-4alkyloxy, C.sub.1-4alkyloxyC.sub.1-4alkyl,
trifluoromethyl, pyrrolidinyl, piperidinyl, morpholinyl,
N-methyl-piperazinyl, or 2-oxo-imidazolidin-1-yl.
[0067] Interesting compounds of formula (I) are those compounds of
formula (I) wherein one or more of the following restrictions apply
[0068] a) n is an integer 1, or n is an integer 2; or [0069] b)
R.sup.1 is C.sub.1-6alkyl substituted with a cyclic group selected
from C.sub.3-8cycloalkyl; or [0070] c) R.sup.1 is C.sub.1-6alkyl
substituted with a heterocycle selected from tetrahydropyranyl; or
[0071] d) R.sup.2 is C.sub.1-6alkyl, in particular R.sup.2 is
tert-butyl or --CH.sub.2-tert-butyl; or [0072] e) R.sup.3 is
hydrogen; or [0073] f) R.sup.4 is N-oxy-pyridinyl; or [0074] g)
R.sup.4 is furanyl, thiophenyl, oxadiazolyl, pyridinyl, or
pyridazinyl; each substituted with 1, 2 or 3 substituents each
independently selected from halo; hydroxy; C.sub.1-4alkyl;
C.sub.1-4alkyloxy; polyhaloC.sub.1-4alkyl;
polyhaloC.sub.1-4alkyloxy; cyano; NR.sup.9R.sup.10;
R.sup.11-carbonyl; R.sup.11--SO.sub.2--; or oxadiazolyl optionally
substituted with C.sub.1-4alkyl; wherein R.sup.9 and R.sup.10 are
independently from another selected from hydrogen or
R.sup.11-carbonyl; and wherein R.sup.11 is C.sub.1-4alkyl, amino,
or morpholinyl.
[0075] In an embodiment, the present invention relates to those
compounds of formula (I), the N-oxides, the pharmaceutically
acceptable acid addition salts and the stereochemically isomeric
forms thereof, wherein n is an integer 1 or 2; R.sup.1 is
C.sub.1-6alkyl substituted with C.sub.3-8cycloalkyl or
tetrahydropyranyl; R.sup.2 is C.sub.1-6alkyl; R.sup.3 is hydrogen;
R.sup.4 is N-oxy-pyridinyl, or R.sup.4 is furanyl, thiophenyl,
oxadiazolyl, pyridinyl, or pyridazinyl; each substituted with 1, 2
or 3 substituents each independently selected from halo; hydroxy;
C.sub.1-4alkyl; C.sub.1-4alkyloxy; polyhaloC.sub.1-4alkyl;
polyhaloC.sub.1-4alkyloxy; cyano; NR.sup.9R.sup.10;
R.sup.11-carbonyl; R.sup.11--SO.sub.2--; or oxadiazolyl optionally
substituted with C.sub.1-4alkyl; wherein R.sup.9 and R.sup.10 are
independently from another selected from hydrogen or
R.sup.11-carbonyl; and wherein R.sup.11 is C.sub.1-4alkyl, amino,
or morpholinyl.
[0076] Compounds of formula (I-a), defined as compounds of formula
(I) wherein n represents 1, and compounds of formula (I-b), defined
as compounds of formula (I) wherein n represents 2, can be prepared
by art known S-oxidation of intermediates (A).
##STR00003##
[0077] S-oxidation reactions can be performed using a 30% aqueous
solution of hydrogen peroxide, or by other oxidizing agents such
as, NaIO.sub.4, tert-butyloxychloride, acyl nitrites, sodium
perborate and peracids such as mCPBA (meta-chloroperbenzoic acid).
Sulfides can be oxidized to sulfoxides which can be further
oxidized to sulfones by addition of another equivalent of hydrogen
peroxide, KMnO.sub.4, sodium perborate, potassium hydrogen
persulfate, mCPBA or the like reagents. If enough oxidizing agent
is present, sulfides can be converted directly to sulfones without
isolation of the sulfoxides.
[0078] Compounds of formula (I-b), defined as compounds of formula
(I) wherein n is 2, can be prepared as described in Scheme 1.
##STR00004##
[0079] The condensation reaction for obtaining compounds of formula
(I-b) can be performed under acidic or basic conditions. Under
acidic conditions, the condensation is done in the presence of an
organic acid such as acetic acid, or an inorganic acid such as HCl
or H.sub.2SO.sub.4, or a combination thereof, in a solvent such as
acetic acid, H.sub.2O, methanol, ethanol, dioxane, toluene, or
dichloroethane. Under basic conditions, the condensation reaction
is performed in the presence of an inorganic base such as e.g.
K.sub.2CO.sub.3 in a reaction-inert solvent such as DMSO, or in an
alcoholic NaOH solution The reaction may conveniently be carried
out at a temperature ranging between room temperature and the
reflux temperature of the reaction mixture. Reaction rate and yield
may be enhanced by microwave assisted heating e.g. at 190.degree.
C. in dichloroethane as solvent, possibly eliminating the need of
an additionally added acid or base.
[0080] Intermediates (A) can be prepared as set out below in Scheme
2.
##STR00005##
[0081] The condensation reaction to obtained an intermediate of
formula (A) can be performed under similar conditions as described
in Scheme 1 for obtaining compounds of formula (I-b).
[0082] Intermediates (A) can also be prepared by reacting
intermediate (XVI) with the intermediate (XV), wherein L is a
leaving group such as halo, methanesulfonyloxy, benzenesulfonyloxy,
trifluoromethanesulfonyloxy and the like reactive leaving groups,
in the presence of a suitable base such as Cs.sub.2CO.sub.3 in a
reaction-inert solvent such as e.g. 2-propanone or dioxane.
Depending upon the type of substituents present in intermediate
(XV) it may be necessary to introduce protecting groups in
intermediate (XV) which can be removed after the coupling reaction.
The reaction may also be performed in the presence of a catalyst
such as Pd.sub.2(dba).sub.3 and a suitable ligand such as
Xantphos.
##STR00006##
[0083] The compounds of formula (I) as prepared in the hereinabove
described processes may be synthesized in the form of racemic
mixtures of enantiomers which can be separated from one another
following art-known resolution procedures. Those compounds of
formula (I) that are obtained in racemic form may be converted into
the corresponding diastereomeric salt forms by reaction with a
suitable chiral acid. Said diastereomeric salt forms are
subsequently separated, for example, by selective or fractional
crystallization and the enantiomers are liberated therefrom by
alkali. An alternative manner of separating the enantiomeric forms
of the compounds of formula (I) involves liquid chromatography
using a chiral stationary phase. Said pure stereochemically
isomeric forms may also be derived from the corresponding pure
stereochemically isomeric forms of the appropriate starting
materials, provided that the reaction occurs stereospecifically.
Preferably if a specific stereoisomer is desired, said compound
will be synthesized by stereospecific methods of preparation. These
methods will advantageously employ enantiomerically pure starting
materials.
[0084] The compounds of formula (I), the pharmaceutically
acceptable salts and stereoisomeric forms thereof possess selective
cannabinoid recepter 2 (CB2) agonistic properties as demonstrated
in the Pharmacological Examples. Pharmacological example C.1
describes the methodology to measure CB1 and CB2 agonism and the
ratio of CB2 agonism over CB1 agonism is listed in Table C.1.
[0085] Therefore the present compounds of formula (I) are useful as
a medicine especially in the treatment of a condition or disease
mediated by the cannabinoid 2 receptor, in particular CB2 agonistic
activity. Subsequently the present compounds may be used for the
manufacture of a medicine for treatment of a condition or a disease
mediated by CB2 receptor activity, in particular CB2 agonistic
activity.
[0086] Preferably, the present invention also provides the use of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof for the manufacture of a medicament for the treatment of
conditions or diseases selected from CB2 conditions or
diseases.
[0087] Further, the present invention provides a method of
treatment of a condition mediated by CB2 receptor activity, in a
mammalian subject, which comprises administering to a mammal in
need of such treatment a therapeutically effective amount of a
compound of formula (I) or a pharmaceutically acceptable salt
thereof.
[0088] Cannabinoid receptor 2 mediated conditions or disorders are
e.g. cardiovascular diseases, such as e.g. atherosclerosis,
hypertension, myocardial ischemia; chronic pain disorders, such as
e.g. hyperalgesia, neuropathic pain, peripheral pain, visceral
pain, inflammatory pain, thermal hyperalgesia, nociceptive pain,
fibromyalgia, chronic low back pain, and dental pain; inflammation,
oedema, bladder inflammation, neuroinflammatory diseases, immune
system disorders, autoimmune diseases, multiple sclerosis,
rheumatoid arthritis, gastrointestinal disorders, intestinal
motility disorders, irritable bowel syndrome (IBS), inflammatory
bowel disease (IBD), Crohn's disease, chronic liver injury
(cirrhosis), cancer, prostate cancer, cancer pain, glioma, allergy,
nausea and vomiting, asthma, chronic obstructive pulmonary
diseases, psoriasis, epilepsy, and bone loss disorders, such as
e.g., osteoporosis (hereinafter, referred as `CB2 disorders or
diseases`).
[0089] The term "treating" and "treatment`, as used herein, refers
to curative, palliative and prophylactic treatment, including
reversing, alleviating, inhibiting the progress of, or preventing
the disease, disorder or condition to which such term applies, or
one or more symptoms of such disease, disorder or condition.
[0090] The compounds of the present invention may show less
toxicity, good absorption, distribution, good solubility, less
protein binding affinity other than CB2 receptor, and less
drug-drug interaction by reduced interaction with CYP3A4 en
2D6.
[0091] Additionally the present invention provides pharmaceutical
compositions comprising at least one pharmaceutically acceptable
carrier and a therapeutically effective amount of a compound of
formula (I).
[0092] In order to prepare the pharmaceutical compositions of this
invention, an effective amount of the particular compound, in base
or acid addition salt form, as the active ingredient is combined in
intimate admixture with at least one pharmaceutically acceptable
carrier, which carrier may take a wide variety of forms depending
on the form of preparation desired for administration. These
pharmaceutical compositions are desirably in unitary dosage form
suitable, preferably, for oral administration, rectal
administration, percutaneous administration or parenteral
injection.
[0093] For example in preparing the compositions in oral dosage
form, any of the usual liquid pharmaceutical carriers may be
employed, such as for instance water, glycols, oils, alcohols and
the like in the case of oral liquid preparations such as
suspensions, syrups, elixirs and solutions; or solid pharmaceutical
carriers such as starches, sugars, kaolin, lubricants, binders,
disintegrating agents and the like in the case of powders, pills,
capsules and tablets. Because of their easy administration, tablets
and capsules represent the most advantageous oral dosage unit form,
in which case solid pharmaceutical carriers are obviously employed.
For parenteral injection compositions, the pharmaceutical carrier
will mainly comprise sterile water, although other ingredients may
be included in order to improve solubility of the active
ingredient. Injectable solutions may be prepared for instance by
using a pharmaceutical carrier comprising a saline solution, a
glucose solution or a mixture of both. Injectable suspensions may
also be. prepared by using appropriate liquid carriers, suspending
agents and the like. In compositions suitable for percutaneous
administration, the pharmaceutical carrier may optionally comprise
a penetration enhancing agent and/or a suitable wetting agent,
optionally combined with minor proportions of suitable additives
which do not cause a significant deleterious effect to the skin.
Said additives may be selected in order to facilitate
administration of the active ingredient to the skin and/or be
helpful for preparing the desired compositions. These topical
compositions may be administered in various ways, e.g., as a
transdermal patch, a spot-on or an ointment. Addition salts of the
compounds of formula (I), due to their increased water solubility
over the corresponding base form, are obviously more suitable in
the preparation of aqueous compositions.
[0094] It is especially advantageous to formulate the
pharmaceutical compositions of the invention in dosage unit form
for ease of administration and uniformity of dosage. "Dosage unit
form" as used herein refers to physically discrete units suitable
as unitary dosages, each unit containing a predetermined amount of
active ingredient calculated to produce the desired therapeutic
effect in association with the required pharmaceutical carrier.
Examples of such dosage unit forms are tablets (including scored or
coated tablets), capsules, pills, powder packets, wafers,
injectable solutions or suspensions, teaspoonfuls, tablespoonfuls
and the like, and segregated multiples thereof.
[0095] For oral administration, the pharmaceutical compositions of
the present invention may take the form of solid dose forms, for
example, tablets (both swallowable and chewable forms), capsules or
gelcaps, prepared by conventional means with pharmaceutically
acceptable excipients and carriers such as binding agents (e.g.
pregelatinised maize starch, polyvinylpyrrolidone,
hydroxypropylmethylcellulose and the like), fillers (e.g. lactose,
microcrystalline cellulose, calcium phosphate and the like),
lubricants (e.g. magnesium stearate, talc, silica and the like),
disintegrating agents (e.g. potato starch, sodium starch glycollate
and the like), wetting agents (e.g. sodium laurylsulphate) and the
like. Such tablets may also be coated by methods well known in the
art.
[0096] Liquid preparations for oral administration may take the
form of e.g. solutions, syrups or suspensions, or they may be
formulated as a dry product for admixture with water and/or another
suitable liquid carrier before use. Such liquid preparations may be
prepared by conventional means, optionally with other
pharmaceutically acceptable additives such as suspending agents
(e.g. sorbitol syrup, methylcellulose, hydroxypropylmethylcellulose
or hydrogenated edible fats), emulsifying agents (e.g. lecithin or
acacia), non-aqueous carriers (e.g. almond oil, oily esters or
ethyl alcohol), sweeteners, flavours, masking agents and
preservatives (e.g. methyl or propyl p-hydroxybenzoates or sorbic
acid).
[0097] Pharmaceutically acceptable sweeteners useful in the
pharmaceutical compositions of the invention comprise preferably at
least one intense sweetener such as aspartame, acesulfame
potassium, sodium cyclamate, alitame, a dihydrochalcone sweetener,
monellin, stevioside sucralose
(4,1',6'-trichloro-4,1',6'-trideoxygalactosucrose) or, preferably,
saccharin, sodium or calcium saccharin, and optionally at least one
bulk sweetener such as sorbitol, mannitol, fructose, sucrose,
maltose, isomalt, glucose, hydrogenated glucose syrup, xylitol,
caramel or honey. Intense sweeteners are conveniently used in low
concentrations. For example, in the case of sodium saccharin, the
said concentration may range from about 0.04% to 0.1%
(weight/volume) of the final formulation. The bulk sweetener can
effectively be used in larger concentrations ranging from about 10%
to about 35%, preferably from about 10% to 15% (weight/volume).
[0098] The pharmaceutically acceptable flavours which can mask the
bitter tasting ingredients in the low-dosage formulations are
preferably fruit flavours such as cherry, raspberry, black currant
or strawberry flavour. A combination of two flavours may yield very
good results. In the high-dosage formulations, stronger
pharmaceutically acceptable flavours may be required such as
Caramel Chocolate, Mint Cool, Fantasy and the like. Each flavour
may be present in the final composition in a concentration ranging
from about 0.05% to 1% (weight/volume). Combinations of said strong
flavours are advantageously used. Preferably a flavour is used that
does not undergo any change or loss of taste and/or color under the
circumstances of the formulation.
[0099] The compounds of formula (I) may be formulated for
parenteral administration by injection, conveniently intravenous,
intra-muscular or subcutaneous injection, for example by bolus
injection or continuous intravenous infusion. Formulations for
injection may be presented in unit dosage form, e.g. in ampoules or
multi-dose containers, including an added preservative. They may
take such forms as suspensions, solutions or emulsions in oily or
aqueous vehicles, and may contain formulating agents such as
isotonizing, suspending, stabilizing and/or dispersing agents.
Alternatively, the active ingredient may be present in powder form
for mixing with a suitable vehicle, e.g. sterile pyrogen-free
water, before use.
[0100] The compounds of formula (I) may also be formulated in
rectal compositions such as suppositories or retention enemas, e.g.
containing conventional suppository bases such as cocoa butter
and/or other glycerides.
[0101] Those of skill in the treatment of diseases linked to the
mediation of the cannabinoid receptors will easily determine the
therapeutically effective amount of a compound of formula (I) from
the test results presented hereinafter. In general it is
contemplated that a therapeutically effective dose will be from
about 0.001 mg/kg to about 50 mg/kg of body weight, more preferably
from about 0.01 mg/kg to about 10 mg/kg of body weight of the
patient to be treated. It may be appropriate to administer the
therapeutically effective dose in the form of two or more sub-doses
at appropriate intervals throughout the day. Said sub-doses may be
formulated as unit dosage forms, for example each containing from
about 0.1 mg to about 1000 mg, more particularly from about 1 to
about 500 mg, of the active ingredient per unit dosage form.
[0102] As used herein, a "therapeutically effective amount" of a
compound, is the quantity of a compound which, when administered to
an individual or animal, results in a sufficiently high level of
that compound in the individual or animal to cause a discernible
increase or decrease in stimulation of cannabinoid receptors.
[0103] The exact dosage and frequency of administration depends on
the particular compound of formula (I) used, the particular
condition being treated, the severity of the condition being
treated, the age, weight and general physical condition of the
particular patient as well as the other medication, the patient may
be taking, as is well known to those skilled in the art.
Furthermore, said "therapeutically effective amount" may be lowered
or increased depending on the response of the treated patient
and/or depending on the evaluation of the physician prescribing the
compounds of the instant invention. The effective daily amount
ranges mentioned hereinabove are therefore only guidelines.
EXPERIMENTAL PART
[0104] In the procedures described hereinafter the following
abbreviations were used: `DCM` means dichloromethane; `DMF` means
N,N-dimethyl-formamide; `THF` means tetrahydrofuran; `DIPE` means
diisopropylether, `DMF` means N,N-dimethyl-formamide, `DMSO` means
dimethyl sulfoxide `NaBH.sub.3(CN)` means sodium
cyanotrihydroborate, `mCPBA` means 3-chlorobenzenecarboperoxoic
acid, `Cs.sub.2CO.sub.3` means cesium carbonate, `MgSO.sub.4` means
magnesium sulphate, `NaHCO.sub.3` means carbonic acid monosodium
salt, `NaBH.sub.4` means sodium tetrahydroborate(-1),
`Na.sub.2SO.sub.4` means sodium sulfate, `NH.sub.4Cl` means
ammonium chloride, `K.sub.2CO.sub.3` means potassium carbonate,
`NH.sub.4HCO.sub.3` means carbonic acid mono-ammonium salt, `NaOH`
means sodium hydroxide, `NaCl` stands for sodium chloride,
`NaHCO.sub.3` means sodium hydrogen carbonate,
`Pd.sub.2(dba).sub.3` means
tris[.mu.-[(1,2-.eta.:4,5-.eta.)-(1E,4E)-1,5-diphenyl-1,4-pentadien-
-3-one]]dipalladium, `Xantphos` means
(9,9-dimethyl-9H-xanthene-4,5-diyl)bis[diphenylphosphine], `TFA`
means trifluoroacetic acid, `Et.sub.3N` means triethylamine,
`EtOAc` means ethyl acetate, `CH.sub.3OH` means methanol, `PPTS`
means pyridinium p-toluenesulfonate and `PS` means polystyrene.
[0105] Isolute HM-N.TM. filter is a product of Argonaut, Foster
City, Calif. 94404, USA, and is a short column comprising a
modified form of diatomaceous earth that can remove water from a
sample in combinatorial chemistry applications. Extrelut.TM. is a
product of Merck KgaA, Darmstadt, Germany, and is a short column
comprising diatomaceous earth.
[0106] For some compounds that were purified by reversed phase
high-performance liquid chromatography (HPLC) the used method is
described below (indicated in the compound procedure with HPLC
method A, HPLC method B, HPLC method C).
[0107] When necessary, these methods can be slightly adjusted by a
person skilled in the art to obtain a more optimal result for the
separation.
HPLC Method A
[0108] The product was purified by reversed-phase high-performance
liquid chromatography (Shandon Hyperprep.RTM. C18 BDS (Base
Deactivated Silica) 8 .mu.m, 250g, I.D. 5 cm). Three mobile phases
were used (phase A: a 0.25% NH.sub.4HCO.sub.3 solution in water;
phase B: CH.sub.3OH; phase C: CH.sub.3CN). First, 75% A and 25% B
with a flow rate of 40 ml/min was hold for 0.5 minutes. Then a
gradient was applied to 50% B and 50% C in 41 minutes with a flow
rate of 80 ml/min. Then a gradient was applied to 100% C in 20
minutes with a flow rate of 80 ml/min and hold for 4 minutes.
HPLC Method B
[0109] The product was purified by reversed-phase high-performance
liquid chromatography (Shandon Hyperprep.RTM. C18 BDS (Base
Deactivated Silica) 8 .mu.m, 250 g, I.D. 5 cm). Three mobile phases
were used (phase A: a 0.25% NH.sub.4HCO.sub.3 solution in water;
phase B: CH.sub.3OH; phase C: CH.sub.3CN). First, 75% A and 25% B
with a flow rate of 40 ml/min was hold for 0.5 minutes. Then a
gradient was applied to 100% B in 41 minutes with a flow rate of 80
ml/min. Then a gradient was applied to 100% C in 20 minutes with a
flow rate of 80 ml/min and hold for 4 minutes.
HPLC Method C
[0110] The product was purified by reversed-phase high-performance
liquid chromatography (Shandon Hyperprep.RTM. C18 BDS (Base
Deactivated Silica) 8 .mu.m, 250g, I.D. 5 cm). Two mobile phases
were used (phase A: a 0.25% NH.sub.4HCO.sub.3 solution in water;
phase B: CH.sub.3CN). First, 85% A and 15% B with a flow rate of 40
ml/min was hold for 0.5 minutes. Then a gradient was applied to 10%
A and 90% B in 41 minutes with a flow rate of 80 ml/min. Then a
gradient was applied to 100% C in 20 minutes with a flow rate of 80
ml/min and hold for 4 minutes.
A. Synthesis of the Intermediates
Example A.1
a) Preparation of
##STR00007##
[0112] A mixture of 5-chloro-2-nitrobenzenamine (0.16 mol),
4-methoxybenzenemethanethiol (0.16 mol) and potassium hydroxide
(0.30 mol) in ethanol (500 ml) was stirred and refluxed for 2
hours. The reaction mixture was cooled. The precipitate was
filtered off, washed with ethanol and dried, yielding 48.5 g of
intermediate (1).
b) Preparation of
##STR00008##
[0114] 2,2-Dimethylpropanoyl chloride (0.14 mol) was added dropwise
to a mixture of intermediate (1) (0.125 mol) and pyridine (500 ml).
The reaction mixture was stirred and refluxed for 2 hours. The
reaction mixture was cooled and the solvent was evaporated. The
residue was taken up into DCM and washed with water. The organic
layer was separated, dried, filtered and the solvent was
evaporated. The residue was crystallized from DIPE with a drop of
hexane. The precipitate was filtered off, washed and dried,
yielding 28.9 g of intermediate (2).
c) Preparation of
##STR00009##
[0116] A mixture of intermediate (2) (0.0748 mol), Fe powder (56 g)
and acetic acid (10 ml) in water (500 ml) was stirred and refluxed
for 4 hours. The mixture was cooled. The solvent was decanted. The
residue was taken up into methanol and THF. The mixture was
filtered over diatomite. The solvent was evaporated. The residue
was taken up into DCM. The organic layer was separated and filtered
over MgSO.sub.4 and diatomite. The solvent was evaporated. The
residue was crystallized from DIPE. The precipitate was filtered
off and dried, yielding 21g of intermediate (3).
d) Preparation of
##STR00010##
[0118] Nitrogen gas was bubbled through a mixture of intermediate
(3) (0.03 mol), DCM (600 ml) and acetic acid (5 ml) at room
temperature. Cyclohexanecarboxaldehyde (4g) was added. After 5
minutes NaBH.sub.3(CN) (1.8 g) was added. The reaction mixture was
stirred at room temperature for 1 hour. Water was added. The
mixture was extracted. The organic layer was separated, dried,
filtered and the solvent was evaporated. The residue was
crystallized from DIPE. The precipitate was filtered off and dried,
yielding 10.5 g of intermediate (4).
##STR00011##
[0119] Intermediate (81) was prepared in a similar procedure as
intermediate (4) using 3,3-dimethylbutanal.
##STR00012##
[0120] Intermediate (96) was prepared in a similar procedure as
intermediate (4) using 2,2-dimethylpropanal.
##STR00013##
[0121] Intermediate (99) was prepared in a similar procedure as
intermediate (4) using tetrahydro-2H-pyran-4-acetaldehyde.
##STR00014##
[0122] Intermediate (102) was prepared in a similar procedure as
intermediate (4) using tetrahydro-2H-thiopyran-4-carboxaldehyde.
Additionally, titanium (IV) isopropoxide (4:1) was added for the
synthesis of intermediate (102).
[0123] Intermediate (102) was also prepared in a similar procedure
as intermediate (4) using methyl tetrahydro-2H-thiopyran-4-yl
ketone.
##STR00015##
[0124] Intermediate (105) was prepared in a similar procedure as
intermediate (4) using 1,4-dioxaspiro[4.5]decane-8-carboxaldehyde.
Additionally, titanium (IV) isopropoxide (4:1) was added for the
synthesis of intermediate (105).
##STR00016##
[0125] Intermediate (92) was prepared in a similar procedure as
intermediate (4) using cyclobutanecarboxaldehyde. Additionally,
titanium (IV) isopropoxide (4:1) was added for the synthesis of
intermediate (92).
##STR00017##
[0126] Intermediate (119) was prepared in a similar procedure as
intermediate (4) using 2-ethylbutanal.
##STR00018##
[0127] Intermediate (122) was prepared in a similar procedure as
intermediate (4) using 2-methylpentanal.
##STR00019##
[0128] Intermediate (125) was prepared in a similar procedure as
intermediate (4) using
tetrahydro-2,2-dimethyl-2H-pyran-4-carboxaldehyde.
e) Preparation of
##STR00020##
[0130] A mixture of intermediate (4) (0.0045 mol) and acetic acid
(40 ml) was stirred and refluxed for 6 hours. The mixture was
cooled and the solvent was evaporated. The residue was taken up
into DCM and water. The mixture was neutralized with NaHCO.sub.3.
The organic layer was separated, dried, filtered and the solvent
was evaporated. The residue was purified by column chromatography
on silicagel (eluent: DCM/methanol 100/0 to 98/2). The product
fractions were collected and the solvent was evaporated. The
residue was crystallized from DIPE. The precipitate was filtered
off, washed and dried, yielding 1g of intermediate (5).
##STR00021##
[0131] Intermediate (82) was prepared in a similar procedure as
intermediate (5) starting from intermediate (81).
##STR00022##
[0132] Intermediate (97) was prepared in a similar procedure as
intermediate (5) starting from intermediate (96).
##STR00023##
[0133] Intermediate (100) was prepared in a similar procedure as
intermediate (5) starting from intermediate (99).
##STR00024##
[0134] Intermediate (103) was prepared in a similar procedure as
intermediate (5) starting from intermediate (102).
##STR00025##
[0135] Intermediate (106) was prepared in a similar procedure as
intermediate (5) starting from intermediate (105).
##STR00026##
[0136] Intermediate (110) was prepared in a similar procedure as
intermediate (5) starting from intermediate (92).
##STR00027##
[0137] Intermediate (120) was prepared in a similar procedure as
intermediate (5) starting from intermediate (119).
##STR00028##
[0138] Intermediate (123) was prepared in a similar procedure as
intermediate (5) starting from intermediate (122). Additionally, a
few drops of HCl were added to the reaction mixture.
##STR00029##
[0139] Intermediate (126) was prepared in a similar procedure as
intermediate (5) starting from intermediate (125).
f) Preparation of
##STR00030##
[0141] A mixture of intermediate (5) (0.019 mol) and
trifluoroacetic acid (200 ml) was stirred and refluxed for 5 hours.
The mixture was cooled and the solvent was evaporated. The residue
was taken up into ethyl acetate and water. The mixture was
neutralized with NaHCO.sub.3. The organic layer was separated,
dried, filtered and the solvent was evaporated, yielding 8g of
intermediate.(6).
##STR00031##
[0142] Intermediate (83) was prepared in a similar procedure as
intermediate (6) starting from intermediate (82).
##STR00032##
[0143] Intermediate (98) was prepared in a similar procedure as
intermediate (6) starting from intermediate (97).
##STR00033##
[0144] Intermediate (101) was prepared in a similar procedure as
intermediate (6) starting from intermediate (100).
##STR00034##
[0145] Intermediate (104) was prepared in a similar procedure as
intermediate (6) starting from intermediate (103).
##STR00035##
[0146] Intermediate (118) was prepared in a similar procedure as
intermediate (6) starting from intermediate (106).
##STR00036##
[0147] Intermediate (111) was prepared in a similar procedure as
intermediate (6) starting from intermediate (110).
##STR00037##
[0148] Intermediate (121) was prepared in a similar procedure as
intermediate (6) starting from intermediate (120).
##STR00038##
[0149] Intermediate (124) was prepared in a similar procedure as
intermediate (6) starting from intermediate (123).
##STR00039##
[0150] Intermediate (127) was prepared in a similar procedure as
intermediate (6) starting from intermediate (126).
Example A.2
a) Preparation of
##STR00040##
[0152] Nitrogen gas was bubbled through a mixture of intermediate
(3) (0.032 mol), DCM (650 ml) and acetic acid (5 ml) at room
temperature. Tetrahydro-2H-pyran-4-carboxaldehyde (0.039 mol) was
added. After 5 minutes NaBH.sub.3(CN) (2g) was added. The reaction
mixture was stirred at room temperature for 1 hour. Water was
added. The mixture was extracted. The organic layer was separated,
dried, filtered and the solvent was evaporated. The residue was
crystallized from DIPE. The precipitate was filtered off and dried,
yielding 12 g of intermediate (7).
b) Preparation of
##STR00041##
[0154] A mixture of intermediate (7) (0.027 mol) and acetic acid
(200 ml) was stirred and refluxed for 6 hours. The mixture was
cooled and the solvent was evaporated. The residue was taken up
into DCM and water. The mixture was neutralized with NaHCO.sub.3.
The organic layer was separated, dried, filtered and the solvent
was evaporated. The residue was purified by column chromatography
(eluent: DCM/CH.sub.3OH 100/0 to 96/4). The product fractions were
collected and the solvent was evaporated. The residue was
crystallized from DIPE. The precipitate was filtered off, washed
and dried, yielding 8 g of intermediate (8).
c) Preparation of
##STR00042##
[0156] A mixture of intermediate (8) (0.019 mol) in trifluoroacetic
acid (200 ml) was stirred and refluxed for 5 hours. The mixture was
cooled and the solvent was evaporated. The residue was taken up
into ethyl acetate and water. The mixture was neutralized with
NaHCO.sub.3. The organic layer was separated, dried, filtered and
the solvent was evaporated, yielding 7 g of intermediate (9).
Example A.3
a) Preparation of
##STR00043##
[0158] 3,3-Dimethylbutanoyl chloride (0.20 mol) was added dropwise
to a mixture of intermediate (1) (0.16 mol) in pyridine (600 ml) at
room temperature and stirred for 1 hour at room temperature. The
solvent was evaporated. The residue was taken up in DCM. This
mixture was washed with water, diluted HCl aqueous solution and
with diluted NH.sub.4Cl aqueous solution. The separated organic
layer was dried, filtered and the solvent was evaporated, yielding
62 g of intermediate (10).
b) Preparation of
##STR00044##
[0160] A mixture of intermediate (10) (0.12 mol) in THF (500 ml)
was hydrogenated at a temperature below 30.degree. C. with a
mixture of platinum on activated carbon (5%)+vanadium pentoxide
(0.5%) (5g) as a catalyst. After uptake of hydrogen (3 equiv.), the
catalyst was filtered off and the filtrate's solvent was
evaporated. The residue was suspended in DIPE. The precipitate was
filtered off, washed and dried, yielding 39g of intermediate
(11)
c) Preparation of
##STR00045##
[0162] A mixture of intermediate (11) (0.07 mol) in DCM (1300 ml)
and acetic acid (10 ml) at room temperature was bubbled with
nitrogen. Tetrahydro-2H-pyran-4-carboxaldehyde (0.088 mol) was
added at room temperature to the reaction mixture and stirred for
30 minutes at room temperature. Sodium cyanotrihydroborate (4.5 g)
was added in 10 portions at room temperature. The reaction mixture
was stirred for 30 minutes. Water was added and after extraction,
the separated organic layer was dried, filtered and the solvent was
evaporated. The residue was suspended in DIPE. The precipitate was
filtered off, washed and dried, yielding 23.5 g of intermediate
(12).
##STR00046##
[0163] Intermediate (76) was prepared in a similar procedure as
intermediate (12) using tetrahydro-2H-pyran-2-carboxaldehyde.
d) Preparation of
##STR00047##
[0165] Intermediate (12) (0.051 mol) in acetic acid (500 ml) was
stirred for 2 hours at reflux temperature. The reaction mixture was
cooled and the solvent was evaporated. The residue was taken up in
DCM and water. This mixture was neutralized to pH=7 with
NaHCO.sub.3. After extraction, the separated organic layer was
dried, filtered and the solvent was evaporated, yielding 23g of
intermediate (13).
##STR00048##
[0166] Intermediate (77) was prepared in a similar procedure as
intermediate (13) starting from intermediate (76).
e) Preparation of
##STR00049##
[0168] Intermediate (13) (0.0044 mol) in trifluoroacetic acid (20
ml) was heated in a microwave at 150.degree. C. for 15 minutes. The
reaction mixture was cooled and the solvent was evaporated. The
residue was taken up in ethyl acetate and water. This mixture was
neutralized to pH=7 with NaHCO.sub.3. After extraction, the
separated organic layer was dried, filtered and the solvent was
evaporated, yielding 2.2 g of intermediate (14).
##STR00050##
[0169] Intermediate (78) was prepared in a similar procedure as
intermediate (14) starting from intermediate (77).
Example A.4
a) Preparation of
##STR00051##
[0171] 2,2-Dimethylbutyric acid chloride (0.2 mol) was added to
intermediate (1) (0.18 mol) in pyridine (550 ml). The reaction
mixture was stirred and refluxed for 2 hours. The reaction mixture
was cooled and the solvent was evaporated. The residue was
partitioned between water and DCM. The organic layer was separated,
dried, filtered and the solvent was evaporated. The residue was
suspended in DIPE. The resulting precipitate was filtered off and
dried, yielding 62g of intermediate (15).
b) Preparation of
##STR00052##
[0173] A mixture of intermediate (15) (0.16 mol) in THF (500 ml)
was hydrogenated at 25.degree. C. with platinum-on-carbon (5%, 5g)
as a catalyst in the presence of a small quantity of
V.sub.2O.sub.5. After uptake of hydrogen, the catalyst was filtered
off and to the filtrate, extra platinum-on-carbon (5%, 5g) and a
small quantity of V.sub.2O.sub.5 were added. The hydrogenation was
continued until hydrogen (3 equiv.) were taken up. The catalyst was
filtered off and the filtrate was evaporated. The residue was
suspended in DIPE, filtered off and dried, yielding intermediate
(16).
c) Preparation of
##STR00053##
[0175] A mixture of intermediate (16) (0.056 mol) in acetic acid
(300 ml) was stirred and refluxed for 3 hours, then cooled and the
solvent was evaporated. The residue was partitioned between water
and DCM. The mixture was neutralized with an aqueous NaHCO.sub.3
solution. The organic layer was separated, dried, filtered and the
solvent was evaporated. Part (2.5 g) of the residue was dissolved
in ethanol (50 ml). NaBH.sub.4 (0.160g) was added and the reaction
mixture was stirred and refluxed for 2 hours. Extra NaBH.sub.4
(0.500g) was added and the reaction mixture was stirred and
refluxed for 20 hours. The remaining residue was dissolved in
ethanol. NaBH.sub.4 (6 g) was added and the reaction mixture was
stirred and refluxed for 20 hours. The reaction mixture was cooled.
Water was added The solvent was evaporated. The residue was
partitioned between water and DCM. The organic layer was separated,
dried, filtered and the solvent was evaporated. The residue was
suspended in DIPE, filtered off and dried, yielding 15 g of
intermediate (17).
d) Preparation of
##STR00054##
[0177] Reaction under nitrogen atmosphere. A solution of
intermediate (17) (0.021 mol) in THF (250 ml) was stirred.
Sodiumhydride (0.025 mol) was added and the reaction mixture was
stirred for 30 minutes at 40.degree. C. Cyclobutylmethyl bromide
(0.025 mol) was added and the reaction mixture was stirred for 2
hours at 40.degree. C. More cyclobutyl-methyl bromide (1 equiv.)
was added and the reaction mixture was stirred for 20 hours at
60.degree. C. More sodium hydride (0.3 g) was added. Extra
cyclobutylmethyl bromide (1 g) was added and the reaction mixture
was stirred for 20 hours at 60.degree. C. Extra sodium hydride (0.3
g) was added, followed by addition of cyclobutylmethyl bromide
(1g). Upon reaction completion, the reaction mixture was cooled.
The solvent was evaporated. The residue was partitioned between
water and DCM. The organic layer was separated, dried, filtered and
the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH
99/1). The product fractions were collected and the solvent was
evaporated, yielding 1.2 g of intermediate (18).
e) Preparation of
##STR00055##
[0179] Reaction in microwave oven. Intermediate (18) (0.003 mol) in
trifluoroacetic acid (15 ml) was heated for 15 minutes at
110.degree. C. The reaction mixture was cooled and the solvent was
evaporated. The residue was partitioned between water and ethyl
acetate. The mixture was neutralized with an aqueous NaHCO.sub.3
solution. The organic layer was separated, dried, filtered and the
solvent was evaporated, yielding intermediate (19).
Example A.5
Preparation of
##STR00056##
[0181] A mixture of morpholine (0.007 mol) in THF (30 ml) and
triethylamine (0.800 g) was stirred at room temperature. A solution
of 5-bromo-2-thiophenesulfonyl chloride (0.005 mol) in THF (10 ml)
was added slowly at room temperature. The reaction mixture was
stirred overnight at room temperature in a closed reaction vessel.
Then, the mixture was taken up into ethyl acetate, washed with
water, with 1 N HCl (20 ml), with a saturated aqueous NaHCO.sub.3
solution, then dried, filtered and the solvent was evaporated,
yielding 1.6 g of intermediate (20).
Example A.6
Preparation of
##STR00057##
[0183] Ammonia was bubbled in excess through a THF (20 ml)
solution. A solution of 2-bromo-5-furancarbonyl chloride (0.005
mol) in THF (10 ml) was added dropwise. The resultant reaction
mixture was stirred for 3 hours at 50.degree. C. DCM (100 ml) was
added. Water (40 ml) was added. The biphasic mixture was shaken for
a while. The layers were separated. The organic layer was dried,
filtered and the solvent was evaporated, yielding 0.970 g of
intermediate (21).
Example A.7
Preparation of
##STR00058##
[0185] Reaction under Argon flow. Intermediate (8) (0.00235 mol)
was dissolved in degassed trifluoroacetic acid (20 ml) and stirred
overnight at 80.degree. C. The solvent was evaporated. The residue
was taken up in degassed toluene. The mixture was washed with
degassed saturated aqueous NaHCO.sub.3 solution. The organic layer
was separated, dried, filtered and the solvent was evaporated. The
residue was dissolved in degassed dioxane (20 ml).
3-Bromo-2,4-pentanedione (0.00235 mol) and Cs.sub.2CO.sub.3 (1.15
g) were added. The reaction mixture was stirred at 100.degree. C.
for 3 hours. The reaction mixture was cooled and the solvent was
evaporated. The residue was taken up in ethyl acetate. The organic
layer was separated, washed with water and then with brine, dried,
filtered and the solvent was evaporated. The residue was purified
by column chromatography over silica gel (eluent: hexane/ethyl
acetate 1/2). The product fractions were collected and the solvent
was evaporated, yielding 0.090 g of intermediate (22).
Example A.8
Preparation of
##STR00059##
[0187] A mixture of intermediate (9) (0.002 mol) and
5-bromo-2-thiophenesulfonamide (0.0025 mol) in dioxane (40 ml) was
degassed and a flow of nitrogen was brought over the reaction
mixture (3 times). Then Cs.sub.2CO.sub.3 (0.004 mol) was added and
the mixture was degassed and nitrogen was brought over the reaction
mixture again. (twice). Then Pd.sub.2(dba).sub.3 (0.0001 mol) and
Xantphos (0.0001 mol) were added and degassing and the nitrogen
action were performed (twice). A nitrogen balloon was left on the
reaction mixture and the mixture was stirred overnight at
100.degree. C. The mixture was cooled, filtered and the filtrate
was evaporated, yielding intermediate (25).
[0188] The heterocyclic reagent 5-bromo-2-thiophenesulfonamide can
be replaced by other heterocycles such as e.g.
5-bromo-2(1H)-pyridinone, 4-chloro-pyridine hydrochloride,
1-(6-chloro-3-pyridinyl-1-ethanone, 5-bromo-2-thiophenesulfonamide,
3-(bromo-3-thienyl)-5-methyl-1,2,4-oxadiazole,
2-(ethylsulfonyl)-5-iodo-thiophene, 4-bromo-1H-pyridin-2-one,
4-bromo-2-ethoxy-pyridine, 2,4,6-trichloropyridine,
4-chloro-2-methyl-pyridine, 3-chloro-6-methoxy-pyridazine,
4-chloro-3-(trifluoromethyl)pyridine hydrochloride,
N-(4-chloro-2-pyridinyl)-acetamide, 4-bromo-2-methyl-pyridine,
4-bromo-2-fluoro-pyridine, 1-(5-bromopyridin-2-yl)ethanone,
2-methylsulfonyl-5-bromopyridine, intermediate (20), intermediate
(21), 4-bromo-2-chloropyridine, 2-chloro-4-pyrimidinecarboxamide,
6-chloro-3-pyridinecarboxylic acid, methyl ester,
5-bromo-3-pyridinecarbonitrile, 5-bromo-2(1H)-pyridinone,
1-(5-bromo-2-thienyl)-ethanon, 5-bromo-2-thiophenecarbonitrile,
5-bromo-2-pyridinecarbonitrile], 1-(4-iodophenyl)-ethanone,
5-bromo-2-methoxy-pyridine, 2-(4-bromo-2-furanyl)-1,3-dioxolan,
5-bromo-2-(methylsulfonyl)pyridine,
2-bromo-5-(methylsulfonyl)thiophene,
5-bromo-N-ethyl-2-thiophenesulfonamide,
5-bromo-2-furancarbonitrile, intermediate 34,
4-[(4,5-dibromo-2-thienyl)sulfonyl]morpholine,
4-[(6-chloro-3-pyridinyl)sulfonyl]-morpholine,
2-chloro-5-(methylsulfonyl)pyridine, intermediate 36,
5-bromo-2-thiophenecarboxamide,
1-[(5-bromo-2-furanyl)carbonyl]pyrrolidine,
3-chlorobenzene-carboperoxoic acid,
4-[(5-bromo-2-thienyl)carbonyl]morpholine,
4-[(5-bromo-2-furanyl)carbonyl]morpholine,
5-bromo-4-methyl-2-thiophenecarboxylic acid, methyl ester,
4-[(4,5-dibromo-2-thienyl)sulfonyl]morpholine,
3-chloro-6-methoxypyridazine, 6-bromo-2-pyridinecarbonitrile,
4-bromo-2-methylpyridine, 4-chloro-2-methyl-pyrimidine,
4-bromo-2-fluoropyridine, 4-bromo-3-methoxypyridine,
3-iodo-2-(trifluoromethyl)pyridine, intermediate (84), intermediate
(116), 4-chloropyridine hydrochloride (1:1), intermediate (129),
intermediate (135), 2-chloro-5-thiazole-carbonitrile,
4-bromo-2(1H)-pyridinone and 4-bromo-2-ethoxypyridine for the
preparation of other compounds of the invention.
[0189] The starting material intermediate (9) can be replaced by
other intermediates such as e.g. intermediate (6), intermediate
(14), intermediate (62), intermediate (66), intermediate (70),
intermediate (78), intermediate (83), intermediate (98),
intermediate (101), intermediate (104), intermediate (111),
intermediate (118), intermediate (121), intermediate (124),
intermediate (127) for the preparation of other compounds of the
invention.
[0190] The following intermediates are prepared according to a
similar procedure as intermediate (25) (Example A.8) starting from
intermediate (9) and a variable heterocyclic reagent as indicated
were used.
##STR00060## ##STR00061##
[0191] The following intermediate was also prepared according to a
similar procedure as intermediate (25) (Example A.8), but starting
from intermediate (111) and 4-bromo-2-fluoropyridine (as the
heterocyclic reagent)
##STR00062##
Example A.9
a) Preparation of
##STR00063##
[0193] Cs.sub.2CO.sub.3 (0.0061 mol) was added to
4-bromo-2(1H)-pyridinone (0.004 mol) in dioxane (10 ml). The
mixture was degassed three times with nitrogen. A degassed solution
of intermediate (9) (0.0023 mol) in dioxane (10 ml) was added. The
reaction mixture was degassed once more. Pd.sub.2(dba).sub.3 (0.047
g) and Xantphos (0.060 g) were added. The reaction mixture was
degassed, then stirred overnight at 100.degree. C. The reaction
mixture was cooled. DCM (150 ml) was added. A 5% aqueous NH.sub.4Cl
solution (150 ml) was added and mixed. The layers were separated.
The aqueous phase was extracted with DCM (100 ml). The combined
organic layers were dried, filtered and the solvent was evaporated.
The residue was purified by CombiFlash flash column chromatography
(eluent: CH.sub.2Cl.sub.2/CH.sub.3OH from 100/0 to 94/6). The
product fractions were collected and the solvent was evaporated,
yielding 0.93 g of intermediate (26).
b-1) Preparation
##STR00064##
[0194] and
##STR00065##
[0195] A mixture of intermediate (26) (0.005 mol),
chlorodifluoroacetic acid sodium salt (0.01 mol) and
K.sub.2CO.sub.3 (0.006 ml) in DMF/H.sub.2O (5 ml) was degassed for
15 minutes. The reaction mixture was stirred overnight at
100.degree. C. The reaction mixture was cooled and a mixture (4 ml)
of HCl 12N and water (ratio 1/1.5) was added. The separated organic
layer was dried, filtered and the solvent was evaporated. The
residue was purified by reversed-phase HPLC (gradient elution with
NH.sub.4HCO.sub.3 buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN).
Two different product fractions were collected and worked-up,
yielding crude intermediate (43) (used as such in the next
reaction) and 0.221 g of intermediate (27).
b-2) Preparation of
##STR00066##
[0196] and
##STR00067##
[0197] 1,1,1-Trifluoro-2-iodoethane (0.0075 mol) was added to a
mixture of intermediate (26)(0.005 mol) and sodium hydride (0.006
mol) in DMF (5 ml). The reaction mixture was stirred at 0.degree.
C. for 4 hours. The reaction mixture was partitioned between DCM
and water. The separated organic layer was dried (MgSO.sub.4),
filtered and the solvent was evaporated. The residue was purified
by reversed-phase HPLC (gradient elution with NH.sub.4HCO.sub.3
buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN). The desired product
fractions were collected and worked-up, yielding 0.176 g of
intermediate (48) (E-isomer) and 0.367 g intermediate (47)
(Z-isomer).
b-3) Preparation of
##STR00068##
[0199] A mixture of intermediate (26) (0.000722 mol),
2,2,2-trifluoro-ethanol, 1-(4-methyl-benzenesulfonate) (0.00144
mol) and potassium carbonate (0.132 g) in DMF (5 ml) was heated to
60.degree. C. The reaction mixture was extracted with DCM/water.
The separated organic layer was dried, filtered and the solvent was
evaporated. The residue was purified by reversed-phase HPLC
(gradient elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The desired product fraction was
collected and the solvent was evaporated, yielding 0.116 g of
intermediate (55).
[0200] Intermediate (58) was prepared in a similar procedure as
intermediate (55), starting from intermediate (23) and
1,1,2,2,3,3,4,4,4-nonafluoro-1-butanesulfonic acid,
2,2,2-trifluoroethyl ester.
##STR00069##
Example A.10
Preparation of
##STR00070##
[0202] Hydroxylamine hydrochloride (0.000211 mol) and then water
(0.5 ml) were added to a solution of intermediate (22) (0.000211
mol) dissolved in methanol (3.5 ml) and stirred overnight at a
temperature between 60.degree. C. and 70.degree. C. The reaction
mixture was cooled and diluted with chloroform. The separated
organic layer was dried, filtered and the solvent was evaporated.
The residue was purified by column chromatography over silica gel
(eluent: ethyl acetate/hexane 50/50). The product fractions were
collected and the solvent was evaporated, yielding 0.050 g of
intermediate (28).
Example A.11
a) Preparation of
##STR00071##
[0204] Cs.sub.2CO.sub.3 (0.0032 mol) was added to
4-chloro-2-pyridinecarboxamide (0.00318 mol) in dioxane (10 ml).
The mixture was degassed three times using nitrogen. A degassed
solution of intermediate (9) (0.003 mol) in dioxane (10 ml) was
added. The reaction mixture was degassed once more.
Pd.sub.2(dba).sub.3 (0.100 g) and Xantphos (0.130 g) were added.
The reaction mixture was degassed, then put in a sealed reaction
vessel under nitrogen atmosphere, then stirred overnight at
100.degree. C. The reaction mixture was cooled, and water (200 ml)
was added. This mixture was extracted with DCM (2.times.150 ml).
The combined organic layers were dried, filtered and the solvent
was evaporated. The residue was purified by reversed-phase HPLC.
The product fractions were collected and the solvent was
evaporated, yielding 0.6 g of intermediate (29).
b) Preparation of
##STR00072##
[0206] Intermediate (29) (0.00075 mol) in DMF (5 ml) was cooled on
an ice-bath. Phosphoric trichloride (0.0016 mol) was added
dropwise. The reaction mixture was stirred for 4 hours at a
temperature between 0.degree. C. and 5.degree. C. The reaction
mixture was poured out into ice-water (75 ml). The pH was
neutralized by addition of NaHCO.sub.3. The resulting precipitate
was filtered off, washed with water, and dried, yielding 0.270g of
intermediate (30).
Example A.12
Preparation of
##STR00073##
[0208] A mixture of intermediate (26) (0.000722 mol),
2,2,2-trifluoroethanol, 4-methyl-benzenesulfonate (0.00144 mol) and
K.sub.2CO.sub.3 (0.132 g) in DMF (3 ml) was heated to 60.degree. C.
The reaction mixture was extracted using DCM and water. The
separated organic layer was dried, filtered and the solvent was
evaporated. The residue was purified by reversed-phase HPLC
(gradient elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and the solvents were evaporated, yielding 0.085 g of intermediate
(31).
Example A.13
Preparation of
##STR00074##
[0210] A mixture of intermediate (9) (max. 0.0016 mol),
6-chloro-3-pyridinecarboxylic acid methyl ester (0.004 mol) and
Cs.sub.2CO.sub.3 (0.003 mol) in dioxane (10 ml) was stirred
overnight at room temperature. The solvent was evaporated under a
stream of N.sub.2. The residue was partitioned between DCM and
water. The separated organic layer was dried by passing through an
Isolute filter and the solvent was evaporated. The residue was
purified by reversed-phase HPLC. The product fractions were
collected and the solvent was evaporated, yielding 0.344 g of
intermediate (32)
[0211] The heterocyclic reagent 6-chloro-3-pyridinecarboxylic acid,
methyl ester can be replaced by other heterocycles such as e.g.
2-chloro-5-(trifluoromethyl)pyridine,
2-chloro-3-pyridinecarbonitrile,
2-chloro-4-(trifluoromethyl)pyridine,
2-chloro-6-(trifluoromethyl)pyridine for the preparation of other
intermediates.
Example A.14
Preparation of
##STR00075##
[0213] A mixture of sodium hydrogen carbonate (0.570 g) and sodium
sulfite (0.800 g) in water (15 ml) was stirred. A solution of
4,5-dibromo-2-thiophenesulfonyl chloride (0.005 mol) in THF (10 ml)
was added. The resultant mixture was stirred for 2 hours at
75.degree. C. Then, the mixture was cooled to 30.degree. C.
Iodomethane (1.4 ml) was added and the resultant reaction mixture
was stirred overnight at 50.degree. C., then cooled, taken up into
ethyl acetate, washed with water and the layers were separated. The
aqueous phase was extracted once more with ethyl acetate. The
organic layers were combined, dried, filtered and the solvent was
evaporated, yielding 1.120 g of intermediate (34).
Example A.15
a) Preparation of
##STR00076##
[0215] mCPBA (77%) (5.7 g) was added to a mixture of
2-methyl-3-(methylthio)furan (1.4 g, 0.011 mol) in chloroform (50
ml) at room temperature (slightly exothermic). The reaction mixture
was stirred for 2 hours and was then washed with water and a NaOH
solution (30%). The separated organic layer was dried (MgSO.sub.4),
filtered and the solvent was evaporated, yielding 1.75 g of
intermediate (35).
b) Preparation of
##STR00077##
[0217] Intermediate (35) (0.004 mol) was stirred in DMF (7 ml).
1-Bromo-2,5-pyrrolidinedione (0.0048 mol) was added carefully over
a 2-minutes period. The reaction mixture was stirred for one hour.
The mixture was poured out into water and this mixture was
extracted with ethyl acetate. The separated organic layer was dried
(MgSO.sub.4), filtered and the solvent evaporated, yielding 1.00 g
of intermediate (36).
Example A.16
Preparation of
##STR00078##
[0218] and
##STR00079##
[0219] A mixture of intermediate (26) (0.00116 mol) and sodium
hydride in mineral oil (60%) (0.0015 mol) in DMF (10 ml) was
stirred for 30 minutes at 60.degree. C. Then the mixture was cooled
to room temperature. Iodomethane (0.0015 mol) was added and the
resultant reaction mixture was shaken overnight at room
temperature. Ethyl acetate (100 ml) was added. Water (100 ml) was
added and the whole was mixed. The layers were separated. The
aqueous phase was extracted with ethyl acetate (100 ml). The
combined organic layers were dried (MgSO.sub.4), filtered and the
solvent was evaporated. The residue was purified by reversed-phase
HPLC. Two product fraction groups were collected and their solvent
was evaporated, yielding 0.36 g of intermediate (37) and 0.015 g of
intermediate (38).
Example A.17
Preparation of
##STR00080##
[0221] A mixture of 2,4,6-trichloropyridine (0.01034 mol),
Cs.sub.2CO.sub.3 (3.3 g), Pd.sub.2(dba).sub.3 (0.130 g) and
Xantphos (0.163 g) in degassed dioxane was stirred. A solution of
intermediate (9) (0.0047 mol) in dioxane was added. The reaction
mixture was heated for 20 hours at 100.degree. C., then cooled,
filtered and the filtrate's solvent was evaporated. The residue was
partitioned between water and DCM. The organic layer was separated,
dried, filtered and the solvent evaporated, yielding of
intermediate (39) as a mixture of region-isomers.
Example A.18
Preparation of
##STR00081##
[0223] All apparatus was flushed with N.sub.2 and dried by heating.
Reaction under Ar flow. Intermediate (8) (0.00187 mol) was
dissolved in degassed TFA (15 ml), then stirred for 4 hours at
85.degree. C. The mixture was cooled. The solvent was evaporated in
vacuo. The residue was taken up into degassed toluene. The organic
layer was separated, washed with a degassed aqueous NaHCO.sub.3
solution (2.times.50 ml), dried, filtered and the solvent was
evaporated in vacuo to give a yellow foam (*). Under Ar,
4-bromo-5-fluoro-2-methoxypyridine (1.3 equiv.; 0.500 g) was
dissolved in degassed dioxane (10 ml). Cs.sub.2CO.sub.3 (0.914 g)
was added to give suspension (**). A solution of the crude residual
oil (*) in degassed dioxane (10 ml) was added to the suspension
(**). Then, Pd.sub.2(dba).sub.3 (0.029 g) and Xantphos (0.032 g)
were added. The resultant brown reaction suspension was stirred
overnight at 100.degree. C. The reaction mixture was cooled, and
the solvent was evaporated. The residue was dissolved in ethyl
acetate, then washed with an aqueous NaHCO.sub.3 solution, and once
with brine. The organic layer was separated, dried, filtered and
the solvent was evaporated. The residue was purified by column
chromatography over silica gel. The product fractions were
collected and the solvent was evaporated, yielding 0.5113 g of
intermediate (40).
Example A.19
a) Preparation of
##STR00082##
[0225] A mixture of NaHCO.sub.3 (0.570 g) and sodium sulfite (0.800
g) in water (15 ml) was stirred. A solution of
5-bromo-6-chloro-3-pyridinesulfonyl chloride (0.005 mol) in THF (10
ml) was added. The resultant mixture was stirred for 2 hours at
75.degree. C. Then, the mixture was cooled to 30.degree. C.
Iodomethane (1.4 ml) was added and the resultant reaction mixture
was stirred overnight at 50.degree. C., then cooled, taken up into
ethyl acetate, washed with water and the layers were separated. The
aqueous phase was extracted once more with ethyl acetate. The
organic layers were combined, dried (MgSO.sub.4), filtered and the
solvent was evaporated, yielding 1.400 g of intermediate (139).
b) Preparation of
##STR00083##
[0227] Cs.sub.2CO.sub.3 (0.00307 mol) was added to intermediate
(139) (0.003 mol) in dioxane (10 ml). The mixture was degassed
((3.times.) vacuum, followed by N.sub.2 inlet). A degassed solution
of intermediate (9) (0.0023 mol) in dioxane (10 ml) was added. The
reaction mixture was degassed once more. Pd.sub.2(dba).sub.3 (0.047
g) and Xantphos (0.060 g) were added. The reaction mixture was
stirred overnight at 100.degree. C. The reaction mixture was
cooled. DCM (150 ml) was added. The organic layer was washed with
water (150 ml). The aqueous layer was extracted again with DCM (150
ml). The combined organic layers were dried (MgSO.sub.4), filtered
and the solvent was evaporated. The residue was purified by
reversed-phase HPLC (gradient elution with NH.sub.4HCO.sub.3 buffer
(0.25% in water)/CH.sub.3OH/CH.sub.3CN). The product fractions were
collected and the solvent was evaporated, yielding 0.83 g of
intermediate (41) as a mixture of two compounds.
Example A.20
Preparation of
##STR00084##
[0229] 4-Bromo-5-fluoro-2(1H)-pyridinone (0.0026 mol) was dissolved
in degassed dioxane (10 ml). Cs.sub.2CO.sub.3 (0.00325 mol) was
added. A solution of intermediate (9) (0.002167 mol) in dioxane (10
ml) was added and the mixture was stirred. Xantphos (0.040 g) and
Pd.sub.2(dba).sub.3 (0.120 g) were added and the resultant reaction
mixture was stirred for 2 hours. The solvent was evaporated in
vacuo. The residue was partitioned between chloroform (100 ml) and
water (2.times.75 ml). The organic layer was separated, washed with
brine (75 ml), dried (Na.sub.2SO.sub.4), filtered and the solvent
was evaporated (vacuum pump). The residue was purified by column
chromatography over silica gel (eluent: ethyl acetate/CH.sub.3OH
9/1). The product fractions were collected and the solvent was
evaporated, yielding 0.474 g of intermediate (42).
Example A.21
a) Preparation of
##STR00085##
[0231] Reaction under nitrogen flow. Phosphoric trichloride (21 ml)
was added drop wise to a mixture at 0.degree. C. of intermediate
(1) (0.13 mol) and 2-cyano-2-methyl-propanoic acid (0.17 mol) in
pyridine (600 ml) while stirring vigorously at 0.degree. C. The
reaction mixture was allowed to warm up to room temperature. Water
(1500 ml) was added. This mixture was extracted with ethyl acetate.
The separated organic layer was dried (MgSO.sub.4), filtered and
the solvent was evaporated, yielding 44g of intermediate (49).
b) Preparation of
##STR00086##
[0233] A mixture of intermediate (49) (0.010 mol) in THF (100 ml)
was hydrogenated at room temperature with a mixture of palladium of
activated carbon (10%) and vanadium pentoxide (0.5%) (5g) as a
catalyst in the presence of a thiophene in DIPE solution (4%) (1
ml). After uptake of hydrogen (3 equivalents), the catalyst was
filtered off and the filtrate was diluted with methanol (300 ml).
Acetic acid (2 ml) and then tetrahydro-2H-pyran-4-carboxaldehyde
(0.015 mol) were added to the mixture. Nitrogen was bubbled through
the reaction mixture for 10 minutes. Sodium cyanotrihydroborate
(400 mg) was added to the reaction mixture. The reaction mixture's
solvent was evaporated to 1/3 of original volume. DCM (700 ml) and
water (500 ml) was added to the concentrate. After extraction, the
separated organic layer was dried (MgSO.sub.4), filtered and the
solvent was evaporated, yielding 4.5 g of intermediate (50).
c) Preparation of
##STR00087##
[0235] Intermediate (50) (0.0066 mol) in acetic acid (15 ml) was
heated in a microwave at 160.degree. C. for 10 minutes. The solvent
was evaporated. The reaction was performed 8 times). All residues
were combined and then taken up in DCM. This mixture was washed
with H.sub.2O/NaHCO.sub.3. After extraction, the separated organic
layer was dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by combiflash column
chromatography over silica gel (eluent: DCM/CH.sub.3OH from 100/0
to 98/2). The product fractions were collected and the solvent was
evaporated, yielding 10.5 g of intermediate (51).
d) Preparation of
##STR00088##
[0237] Intermediate (51) (0.0023 mol) in TFA (10 ml) was heated in
a microwave at 150.degree. C. for 15 minutes. The reaction mixture
was cooled and the solvent was evaporated. The residue was taken up
in ethyl acetate and water and then neutralized with NaHCO.sub.3.
After extraction, the separated organic layer was dried
(MgSO.sub.4), filtered and the solvent was evaporated. This
procedure was repeated another 2 times, resulting in a combined
residue, yielding 3 g of intermediate (52).
e) Preparation of
##STR00089##
[0239] First Pd.sub.2(dba).sub.3 (200 mg), then Xantphos (130 mg)
and finally Cs.sub.2CO.sub.3 (0.003 mol) were added to a mixture of
3-chloro-6-methoxypyridazine (0.007 mol) in dioxane (10 ml) in a
sealed tube and degassed. Intermediate (52) (0.0023 mol;
theoretical, crude) was added and again the reaction mixture was
degassed with N.sub.2. The reaction mixture was stirred for 2 hours
at 100.degree. C. The reaction mixture was cooled and then
filtered. The filtrate's solvent was evaporated. The residue was
purified by combiflash column chromatography over silica gel
(eluent: DCM/CH.sub.3OH from 100/0 to 99/1). The product fractions
were collected and the solvent was evaporated, yielding 0.310 g of
intermediate (53).
Example A.22
Preparation of
##STR00090##
[0241] 4-Chloropyridine N-oxide (0.010 mol) and cesium carbonate
(0.008) were added to a mixture of intermediate (14) (0.0042 mol)
in dioxane (50 ml). The reaction mixture was degassed with nitrogen
and stirred at reflux for 4 hours. The reaction mixture was
filtered over dicalite. The filtrate's solvent was evaporated and
the residue was dried, yielding 3g of intermediate (57).
Example A.23
a) Preparation
##STR00091##
[0243] Reaction under inert argon atmosphere. Intermediate (8) (0.5
g, 0.00117 mol) was dissolved in TFA (98%) (10 ml) and the mixture
was heated overnight at 80.degree. C. The resulting brown solution
was concentrated in vacuo and the residue was taken up in degassed
toluene. The organic layer was washed with NaHCO.sub.3
(saturated),dried (Na.sub.2SO.sub.4) and the solvent was evaporated
to yield a thick yellow oil. This oil was dissolved in THF (5 ml)
and this mixture was added drop wise to a solution of
1,1,1-trifluoro-5-[(tetrahydro-2H-pyran-2-yl)oxy]-3-pentyn-2-one
(0.333 g, 1.2 eq) in THF (5 ml). The yellow mixture was then
stirred for 2 hours at room temperature and then first PPTS (0.03
g, 0.1 eq) and then ethanol (10 ml) were added. The reaction
mixture was stirred at room temperature and an additional amount of
PPTS (0.4 eq) was added. The mixture was heated for 3 hours at
60.degree. C. Then the solvent was evaporated and the residue was
taken up in chloroform. The organic layer was washed with
NaHCO.sub.3 (saturated), water and brine, dried (Na.sub.2SO.sub.4)
and the solvent was evaporated, yielding a brown foam. The crude
product was purified by column chromatography over silica gel
(eluent: ethyl acetate/hexane 3/2). The desired fractions were
collected and the solvent was evaporated, yielding 0.16 g of
intermediate (72) as mixture of two products.
b) Preparation of
##STR00092##
[0245] Intermediate (72) (0.123 g; crude) was dissolved in DCM (4
ml) and the solution was cooled to 0.degree. C. A solution of
hydrobromic acid (33%) in glacial acetic acid was added dropwise
(the yellow mixture turned to slightly brown). Then the reaction
mixture was kept at 0.degree. C. for 2 hours and then the mixture
was quenched with NaHCO.sub.3 (saturated). The crude product was
extracted with DCM. The separated organic layer was washed with
water and brine, dried (Na.sub.2SO.sub.4) and the solvent was
evaporated to yield a brown foam. The crude product was purified by
column chromatography over silica gel (eluent: hexane/ethyl acetate
1/1). The desired fractions were collected and the solvent was
evaporated, yielding 0.044 g of intermediate (73).
Example A.24
a) Preparation of
##STR00093##
[0247] To a mixture of intermediate (3) (0.0290 mol) in acetic acid
(250 ml) were added 4-formyl-1-piperidinecarboxylic acid,
1,1-dimethylethyl ester (0.0468 mol), acetic acid (2 ml) and
titanium (IV) isopropoxide (4:1) (3g). The reaction mixture was
stirred for 20 minutes. Then sodium cyanotrihydroborate (0.03 mol)
was added. The reaction mixture was stirred for 2 hours. Water was
added to the reaction mixture. The organic layer was dried
(MgSO.sub.4), filtered and evaporated, yielding 120g of
intermediate (59).
b) Preparation of
##STR00094##
[0249] A mixture of intermediate (59) (0.071 mol), acetic acid (800
ml) and hydrochloric acid (40 ml) was stirred at reflux overnight.
The reaction mixture was concentrated. The residue was taken up in
DCM and water. Then the mixture was neutralized with NaHCO.sub.3.
The organic layer was dried (MgSO.sub.4), filtered and evaporated.
The residue was used as such in the next reaction, yielding 35g of
intermediate (60).
c-1) Preparation of
##STR00095##
[0251] A mixture of intermediate (60) (0.071 mol), acetic acid,
1,1'-anhydride (0.14 mol) and DCM (700 ml) was stirred at room
temperature for 3 hours. An aqueous NaHCO.sub.3 solution was added
and the mixture was stirred for 1 hour to destroy excess acetic
acid, 1,1'-anhydride. The organic layer was dried (MgSO.sub.4),
filtered and evaporated. The residue was used as such in the next
reaction, yielding 35g of intermediate (61).
c-2) Preparation of
##STR00096##
[0253] A mixture of intermediate (60) (0.026 mol) in formic acid,
methyl ester (300 ml) was stirred and refluxed overnight. The
reaction mixture was cooled and the solvent was evaporated. Toluene
was added and azeotroped on the rotary evaporator, yielding 12 g of
intermediate (65).
d) Preparation of
##STR00097##
[0255] A mixture of intermediate (61) (0.01 mol) and TFA (40 ml)
was stirred in the microwave at 100.degree. C. for 25 minutes. The
reaction mixture was cooled. The solvent was evaporated. The
residue was taken up in ethyl acetate and then washed with a
water/NaHCO.sub.3 solution. The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The crude residue was used
in the next step, yielding 4.7 g of intermediate (62).
e-1) Preparation of
##STR00098##
[0257] N.sub.2 atmosphere. A mixture of intermediate (62) (0.0021
mol), 5-bromo-2-thiophene-carbonitrile (0.004 mol), Xantphos (0.1
g) and Pd.sub.2(dba).sub.3 (0.13 g) in 1,4-dioxane (20 ml) was
degassed. DIPE was added and the reaction mixture was degassed
again. The reaction mixture was stirred at 80-90.degree. C. for 2
hours. After cooling, the reaction mixture was filtered over
dicalite. The filtrate was concentrated and the residue was
purified on silica gel using DCM/CH.sub.3OH (7N NH.sub.3) (from
100% to 99/1) as eluent. The product fractions were collected and
evaporated to dryness. The residue was used as such in the next
reaction, yielding 0.45 g of intermediate (63).
e-2) Preparation of
##STR00099##
[0259] N.sub.2 atmosphere. A mixture of intermediate (62) (0.004
mol), 4-iodo-1-methyl-1H-pyrazole (0.0035 mol), 1,4-dioxane (25 ml)
and Cs.sub.2CO.sub.3 (1.6 g) in Xantphos (0.1 g) was degassed.
Pd.sub.2(dba).sub.3 (0.13 g) was added and the reaction mixture was
degassed again. The reaction mixture was stirred at 80-90.degree.
C. for 2 hours. After cooling, the reaction mixture was filtered
over dicalite. The filtrate was concentrated and the residue was
purified on silica gel using DCM/CH.sub.3OH (from 100% to 96/4) as
eluent. The product fractions were collected and evaporated to
dryness. The residue was used as such in the next reaction,
yielding 0.14 g of intermediate (64).
f) Preparation of
##STR00100##
[0261] A mixture of intermediate (65) (0.00155 mol) in TFA (18 ml)
was stirred at 100.degree. C. for 25 minutes in a microwave oven.
The reaction mixture was concentrated. The residue was partitioned
between an aqueous NaHCO.sub.3 solution and ethyl acetate. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
solvent was evaporated, yielding .+-.0.7 g of intermediate
(66).
g) Preparation of
##STR00101##
[0263] To a mixture of 4-iodo-1-methyl-1H-pyrazole (0.003 mol) and
Cs.sub.2CO.sub.3 (1 g) was added 10 ml dioxane. The mixture was
degassed by applying alternating N.sub.2 atmosphere and vacuum.
Intermediate (66) (0.0022 mol) was added in 10 ml dioxane, and
degassed as above. Pd.sub.2(dba).sub.3 (0.1 g) and Xantphos (0.13
g) were added, degassed again, and the reaction mixture was stirred
under a N.sub.2-atmosphere at 100.degree. C. overnight. The
reaction mixture was cooled, 150 ml water added, and extracted with
2 times with 150 ml of DCM. The combined organic layer was dried
(MgSO.sub.4), filtered, and evaporated. The residue was purified by
HPLC (HPLC method A). The residue was crystallized from DIPE,
yielding 0.195 g of intermediate (67).
Example A.25
a) Preparation of
##STR00102##
[0265] A mixture of intermediate (3) (0.03 mol) and acetic acid
(5.2 ml) in DCM (500 ml) was stirred at room temperature under
N.sub.2-bubbling. 4,4,4-Trifluorobutanal was added. After 15
minutes NaBH.sub.3(CN) was added and the reaction mixture was
stirred for another hour. Water was added and the reaction mixture
was extracted. The separated organic layers were collected, dried
(MgSO.sub.4), filtered and the filtrate was evaporated. The residue
was suspended in DIPE, yielding intermediate (68).
b) Preparation of
##STR00103##
[0267] Intermediate (68) (0.04 mol) was dissolved in acetic acid
(100 ml). The reaction mixture was stirred and refluxed overnight
and the solvent was evaporated. The residue was extracted
(DCM/NaHCO.sub.3), dried, filtered and the solvent was evaporated.
The concentrate was suspended in DIPE and the precipitate was
filtered off and dried, yielding intermediate (69).
c) Preparation of
##STR00104##
[0269] Reaction was performed in microwave Intermediate (69) was
dissolved in TFA. The reaction mixture was stirred for 30 minutes
at 100.degree. C. (10% starting material left). The mixture was
stirred again for 30 minutes at 100.degree. C. The solvent was
evaporated and the residue was extracted (ethyl
acetate/NaHCO.sub.3), dried (MgSO.sub.4), filtered and evaporated.
The concentrate was used crude, yielding intermediate (70).
d) Preparation of
##STR00105##
[0271] A mixture of 4-chloropyridine, 1-oxide (0.0025 mol),
Pd.sub.2(dba).sub.3 (catalytic quantity), Xantphos (catalytic
quantity) and Cs.sub.2CO.sub.3 (0.973 g) in dioxane (5 ml) was
degassed by applying alternating N.sub.2 atmosphere and vacuum.
Intermediate (70) (0.0023 mol) in dioxane (15 ml) was added under
N.sub.2-atmosphere. The reaction mixture was stirred at 100.degree.
C. for 2 hours. The mixture was extracted (DCM/H.sub.2O), dried,
filtered and evaporated. The residue was used crude, yielding
intermediate (71).
Example A.26
a) Preparation of
##STR00106##
[0273] Reaction recipients made inert with N.sub.2. A mixture of
intermediate (8) (0.002355 mol) in TFA (14 ml) was heated at reflux
overnight. The solvent was evaporated. Degassed NaHCO.sub.3
saturated aqueous solution (50 ml) and degassed toluene (80 ml)
were added to the residue. The layers were separated in organic
layer OL1 and in aqueous layer AL1. AL1 was 3 times re-extracted
with toluene (40 ml) to obtain 3 separated organic layers OL2, OL3
and OL4. OL1, OL2, OL3 and OL4 were combined and was dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated
(vacuum, 1 hour) to obtain residue A. The reaction recipients were
made inert with N.sub.2. Cs.sub.2CO.sub.3 (0.00471 mol; dried in
vacuo) was added to a solution of
2-chloro-6-methylpyridine(0.003062 mol) dissolved in DMSO (14 ml)
to obtain mixture A. Then residue A in DMSO (14 ml) was added to
the mixture A. The reaction mixture was degassed for 15 minutes and
then refluxed for 150 minutes. Ethyl acetate was added to the
residue. This mixture was washed 4 times with water (125 ml) and 1
time with NaCl (100 ml). The separated organic layer was dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated. The
residue was purified by column chromatography over silica gel
(eluent: ethyl acetate/hexane 50/50 and 60/40). The product
fractions were collected and the solvent was evaporated, yielding
0.097 g of intermediate (74).
b) Preparation of
##STR00107##
[0275] Reaction recipients made inert with N.sub.2. A mixture of
intermediate (8) (0.002355 mol) in TFA (14 ml) was stirred
overnight at reflux. The solvent was evaporated. The residue was
taken up in degassed toluene (80 ml) and in degassed NaHCO.sub.3
saturated aqueous solution (50 ml). The layers were separated in
organic layer OL1 and in aqueous layer AL1. AL1 was 3 times
re-extracted with toluene (40 ml) to obtain 3 separated organic
layers OL2, OL3 and OL4. OL1, OL2, OL3 and OL4 were combined and
was dried (Na.sub.2SO.sub.4), filtered and the solvent was
evaporated (vacuum, 1 hour) to obtain residue A.
[0276] Reaction recipients made inert with N.sub.2.
Cs.sub.2CO.sub.3 (0.002037 mol; dried in vacuo) was added to a
suspension of 5-bromo-2-methoxypyrimidine (0.003062 mol) in
degassed dioxane (14 ml) to obtain mixture A. Then residue A in
degassed dioxane (14 ml) was added to the mixture A. Finally
Pd.sub.2(dba).sub.3 (0.036 g), Xantphos (0.079 g) and then
potassium fluoride (0.000479 mol) were added and the reaction
mixture was degassed for 15 minutes. The reaction mixture was
stirred at reflux for 19 hours. The solvent was evaporated.
Chloroform was added to the residue. The mixture was washed 2 times
with water and then 1 time with NaCl saturated aqueous solution.
The separated organic layer was dried (Na.sub.2SO.sub.4), filtered
and the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: ethyl acetate/hexane 50/50
and 60/40). The product fractions were collected and the solvent
was evaporated, yielding 0.255 gof intermediate (75).
Example A.27
a) Preparation of
##STR00108##
[0278] Reaction under dry conditions and inert N.sub.2 atmosphere.
A mixture of intermediate (8) (1.5 g, 0.003553 mol) in TFA (20 ml)
was refluxed overnight. The reaction mixture was evaporated and an
extraction procedure was done with NaHCO.sub.3 (degassed saturated
solution) and toluene (4.times., degassed). The separated organic
layer was dried (Na.sub.2SO.sub.4), filtered and the solvent was
evaporated, yielding residue (1). The residue (1) was divided in 2
parts and each part was further treated in a different way.
Reaction A:
[0279] The first part of residue (1) was reacted with
3-bromo-4,4-dimethoxy-2-butanone (0.450 g) in DMF (8 ml; dry) at
0.degree. C. Sodium hydride (60%) (0.051 g) was added. The mixture
was reacted for 30 minutes at 0.degree. C. and then the mixture was
warmed up to room temperature.
[0280] Reaction B: The second part of residue (1) was dissolved in
DMF (3 ml; dry). A suspension of sodium hydride (60%) (0.051 g) in
DMF (2 ml; dry) was added at to the solution at 0.degree. C. The
mixture was reacted for 30 minutes at 0.degree. C. and subsequently
a solution of 3-bromo-4,4-dimethoxy-2-butanone (0.450 g) in DMF (3
ml; dry) was added. The reaction mixture was reacted for 15 minutes
at 0.degree. C. and was then warmed up to room temperature.
[0281] Both reaction mixtures A and B were extracted with ethyl
acetate, NaHCO.sub.3 (saturated solution) and water. The separated
organic layer was dried (Na.sub.2SO.sub.4), filtered and the
solvent was evaporated, yield 0.76 g crude product from reaction A
and 0.74 g crude product from reaction B. Both crude products from
reaction A and reaction B were combined and were purified by column
chromatography over silica gel (eluent: ethyl acetate/hexane first
1/1, then 7/3). The desired fractions were collected and the
solvent was evaporated, yielding intermediate (79).
b) Preparation of
##STR00109##
[0283] Hydrazine dihydrochloride (0.181 g, 0.001728 mol) was added
to a solution of intermediate (79) (0.075 g, 0.000173 mol) and
ethanol (4.5 ml) in a sealed tube and the reaction mixture was
heated at 70-80.degree. C. Subsequently, the mixture was evaporated
and an extraction was done with chloroform, NaHCO.sub.3 (saturated
solution) and water. The separated organic layer was dried
(MgSO.sub.4), filtered and the solvent was evaporated, yielding
0.075 g of the crude product. The crude was purified by preparative
HPLC, yielding 0.057 g of intermediate (80).
Example A.28
Preparation of
##STR00110##
[0285] A mixture of N-(2-hydroxyethyl)acetamide (1g), dioxane (10
ml) and sodium hydride (60%)(0.46 g.) was stirred for 30 minutes at
60.degree. C. The reaction mixture was cooled.
4-Bromo-2-fluoropyridine (1g) was added, and the reaction mixture
was stirred for 90 minutes at 110.degree. C. The reaction mixture
was poured into 100 ml aq. sat. NH.sub.4Cl. The resulting
precipitate was isolated by filtration, washed with water and dried
in vacuo, yielding 1.16 g of intermediate (84).
Example A.29
a) Preparation of
##STR00111##
[0287] A mixture of 4-bromo-2-fluoropyridine (1.1 equiv.),
Pd.sub.2(dba).sub.3 (1.7 g), Xantphos (2.2 g) and Cs.sub.2CO.sub.3
(33g) in dioxane (q.s.) was degassed. A mixture of
4-chlorobenzenethiol (0.062 mol) in dioxane (q.s.) was added. The
reaction mixture was stirred overnight at 100.degree. C. under
N.sub.2 atmosphere. The mixture was filtered and the filtrate's
solvent was evaporated. The residue was partitioned between DCM and
water. The organic layer was separated, dried, filtered and the
solvent evaporated. The residue was purified by flash column
chromatography over silica gel (eluent: hexane/DCM 60/40). The
product fractions were collected and the solvent was evaporated,
yielding intermediate (85).
b) Preparation of
##STR00112##
[0289] 3-Chlorobenzenecarboperoxoic acid (20g) was added to a
mixture of intermediate (85) (0.042 mol) in chloroform. The
reaction mixture was stirred for 30 minutes at room temperature.
This mixture was partitioned between DCM and an aqueous NaOH
solution (2.times.). The organic layer was separated, then filtered
through Extrelut. The filtrate's solvent was evaporated. The
residue was stirred in DIPE, filtered off and dried, yielding
intermediate (86).
c) Preparation of
##STR00113##
[0291] A mixture of intermediate (86) (0.011 mol) in sulphuric acid
(conc.) (35 ml) was stirred and cooled to 0.degree. C. A mixture of
sulphuric acid (conc.) and nitric acid (conc.) (1/1) (5.6 ml) was
added dropwise at 0.degree. C. The resultant reaction mixture was
stirred for 3 hours at room temperature, then poured out into
ice-water. This mixture was extracted with DCM. The separated
organic layer was dried (MgSO.sub.4), filtered and the solvent
evaporated. The residue was suspended in DIPE, filtered off and
dried (vacuum, 40.degree. C.), yielding 1.7 g of intermediate
(87).
d) Preparation of
##STR00114##
[0293] 4,4-Difluoro-cyclohexanemethanamine, trifluoroacetate
(crude, 2 equiv.) in some DMSO was added to a mixture of
intermediate (87) (0.0025 mol, 0.800 g) and
N-ethyl-N-(1-methylethyl)-2-propanamine (0.834 ml) in DMSO (50 ml).
The mixture was stirred for 24 hours at 50.degree. C. Water was
added. This mixture was extracted with ethyl acetate. The separated
organic layer was dried, filtered, and the solvent was evaporated.
The residue was purified by reversed-phase HPLC (gradient elution
with (NH.sub.4OAc 0.5% in water/CH.sub.3CN
90/10)/CH.sub.3OH/CH.sub.3CN). The pure fractions were collected.
The organic solvent was evaporated. The aqueous concentrate was
extracted. The separated organic layer was dried, filtered and the
solvent evaporated, yielding 0.129 g of intermediate (88).
e) Preparation of
##STR00115##
[0295] A mixture of intermediate (88) (0.13 g, 0.0003 mol) in
methanol (50 ml) was hydrogenated with a mixture of platinum on
activated carbon (5%) and vanadium pentoxide (0.5%) (0.1 g) as a
catalyst catalyst in the presence of a thiophene solution (0.1 ml).
After uptake of hydrogen (3 equivalents), the catalyst was filtered
off and the filtrate was evaporated, yielding intermediate
(89).
f) Preparation of
##STR00116##
[0297] Intermediate (89) (0.00024 mol, crude) was dissolved in a
mixture of DCM (5 ml) and triethylamine (0.040 ml).
2,2-Dimethylpropanoyl chloride (0.035 ml) was added and the mixture
was stirred during 30 minutes at room temperature. This mixture was
extracted with DCM. The separated organic layer was washed with
water, dried, filtered and the solvent evaporated, yielding
intermediate (90).
g) Preparation of
##STR00117##
[0299] A mixture of intermediate (90) (0.00024 mol, crude) in
methanol (3 ml) was treated with sodium hydroxide (50%) (7 drops).
The reaction mixture was heated in the microwave oven for 20
minutes at 70.degree. C. The solvent was evaporated, yielding
intermediate (91).
Example A.30
a-1) Preparation of
##STR00118##
[0301] 2-Bromo-4-chloropyridine (0.0025 mol, 0.5 g),
dichlorobis(triphenylphosphine)-palladium (0.055 g, 0.03 equiv.)
and copper iodide (0.015 g, 0.03 equiv.) were combined under
N.sub.2 flow. Triethylamine (6 ml) and ethynyltrimethylsilane
(0.407 ml, 1.1 equiv.) were added at 40.degree. C. The mixture was
stirred overnight at 40.degree. C. The reaction was quenched by
adding water. The mixture was partitioned between DCM and water.
The organic layer was separated, dried (MgSO.sub.4), filtered and
the solvent was evaporated, yielding intermediate (93).
a-2) Preparation of
##STR00119##
[0303] Intermediate (93) (0.0025 mol) was added to a mixture of
potassium hydroxide (0.005 mol, 0.280 g) and methanol (4.25 ml) in
DCM (2.25 ml). The reaction mixture was stirred during 2 hours at
room temperature. The reaction was quenched with water and
subsequently extracted with DCM. The separated organic layer was
dried (MgSO.sub.4), filtered and the solvent evaporated, yielding
intermediate (94).
b) Preparation of
##STR00120##
[0305] A mixture of intermediate (94) (0.0025 mol, crude),
Pd.sub.2(dba).sub.3 (0.063 g, 0.03 equiv.), Xantphos (0.079 g, 0.06
equiv.) and Cs.sub.2CO.sub.3 (1.2 g, 1.5 equiv.) in 1,4-dioxane (20
ml) was degassed. Intermediate (9) (0.0023 mol) was added and the
mixture was stirred overnight at 100.degree. C. The mixture was
cooled and filtered. The filtrate was evaporated. The residue was
dissolved in DCM and this mixture was extracted with water. The
separated organic layer was dried, filtered, and the solvent was
evaporated, yielding intermediate (95).
Example A.31
a) Preparation of
##STR00121##
[0307] A mixture of intermediate (106) (0.02 mol), NaBH.sub.4 (0.28
g) and methanol (100 ml) was stirred at room temperature for 1
hour. The solvent was evaporated. The residue was taken up in DCM
and washed with water. The organic layer was dried (MgSO.sub.4),
filtered and evaporated, yielding 0.6 g of intermediate (107).
b) Preparation of
##STR00122##
[0309] Intermediate (107) (0.0013 mol) and TFA (10 ml) were stirred
in the microwave at 100.degree. C. for 25 minutes. The reaction
mixture was cooled. The solvent was evaporated. The residue was
taken up in ethyl acetate and then washed with water/NaHCO.sub.3
solution. The organic layer was dried (MgSO.sub.4), filtered and
evaporated. The crude residue was used in the next step, yielding
0.6 g of intermediate (108).
c) Preparation of
##STR00123##
[0311] N.sub.2 atmosphere. A mixture of intermediate (108) (0.007
mol), 4-bromo-2-fluoropyridine (0.01 mol), Xantphos (0.15 g) and
Pd.sub.2(dba).sub.3 (0.2 g) in dioxane (50 ml) was degassed.
Cs.sub.2CO.sub.3 (3.3 g) was added and the reaction mixture was
degassed again. The reaction mixture was stirred at 90.degree. C.
for 1 hour. The reaction mixture was filtered over dicalite. The
filtrate was concentrated. The residue was taken up in DCM and
washed with water. The organic layer was dried (MgSO.sub.4),
filtered and evaporated. The residue was purified on the combiflash
system (normal phase silica gel) using DCM /CH.sub.3OH (100% to
96%/4%) as eluent. The product fractions were collected and
evaporated, yielding a residue (1.8 g, mixture of CIS/TRANS 13/80).
A part of this residue (0.35 g) of was purified by HPLC (HPLC
method C) to separate the CIS/TRANS isomers. The desired product
fractions (only the TRANS isomer was used in the next reaction
step) were collected and evaporated until complete dryness,
yielding 0.14 g of intermediate (109) (1,4-trans isomer
(pure)).
Example A.32
a) Preparation of
##STR00124##
[0313] N.sub.2 atmosphere. A mixture of intermediate (9) (0.014
mol), 4-bromo-2-chloropyridine (0.015 mol), Xantphos (0.42 g) and
Pd.sub.2(dba).sub.3 (0.6 g) in dioxane (100 ml) was degassed.
Cs.sub.2CO.sub.3 was added and the reaction mixture was degassed
again. The reaction mixture was stirred at 80-90.degree. C. for 2
hours. The reaction mixture was cooled and filtered over dicalite.
The filtrate was evaporated. The residue was crystallized from DIPE
and a little 2-propanol. The solid was filtered off, washed and
dried, yielding 3.5 g of intermediate (113).
b) Preparation of
##STR00125##
[0315] A mixture of intermediate (113) (0.0005 mol) and
N-methyl-1-butanamine (10 ml) were stirred in the microwave for 12
hours at 150.degree. C. The excess of N-methyl-1-butanamine was
removed by evaporation. The residue was purified by column
chromatography using DCM/MeOH:NH.sub.3 (100% to 98%/2%) as eluent.
The product fractions were collected and evaporated. The residue
was used as such in the next reaction, yielding 0.125 g of
intermediate (114).
Example A.33
a) Preparation of
##STR00126##
[0317] Reaction under N.sub.2 flow. Et.sub.3N (2.5 ml) and then
2-(3-butyn-1-yl)-1H-Isoindole-1,3(2H)-dione (0.0011 mol) were added
at 40.degree. C. to a mixture of 2-bromo-4-chloropyridine (0.001
mol), dichlorobis(triphenylphosphine)-palladium (0.022 g) and
copper iodide (0.006 g) and stirred for 10 hours at 40.degree. C.
The solvent was evaporated. The residue was partitioned between DCM
and water. The mixture was filtered over Isolute and the filtrate's
solvent was evaporated. The residue was purified by column
chromatography (eluent: DCM). The desired product fractions were
collected and the solvent was evaporated. The residue was suspended
in DIPE and the precipitate was filtered off, yielding 0.200 g of
intermediate (115).
##STR00127##
[0318] Intermediate (128) was prepared in a similar procedure as
intermediate (115) starting from 2,4-dichloropyridine and
3-methoxy-1-propyne.
b) Preparation of
##STR00128##
[0320] A mixture of intermediate (115) (0.0026 mol) in methanol (50
ml) was hydrogenated with a catalyst platinum on activated carbon
(5%) and a thiophene (4%) in DIPE solution in the presence
triethylamine. After uptake of hydrogen (2 equiv.) the catalyst was
filtered off and the solvent was evaporated, yielding 0.5 g of
intermediate (116).
##STR00129##
[0321] Intermediate (129) was prepared in a similar procedure as
intermediate (116) starting from intermediate (128). No
triethylamine was used in the procedure for intermediate (129).
Example A.34
a) Preparation of
##STR00130##
[0323] This reaction was performed twice.
[0324] A mixture of 4-methoxycyclohexanecarboxaldehyde (0.0063 mol)
and intermediate (3) (0.0042 mol) was dissolved in ethanol with 1
equiv. hydrogen. After uptake of hydrogen, the reaction mixture was
evaporated.
[0325] The second time, the reaction was performed with less
intermediate (3) (1.23 g). The reaction mixture was extracted
(DCM/water). The collected organic layers were dried, filtered and
evaporated. Both residues were put together and purified by HPLC
(HPLC method A). The desired fractions were collected and the
solvent was evaporated, yielding intermediate (30).
b) Preparation of
##STR00131##
[0327] A solution of intermediate (130) (0.042 mol) in acetic acid
(q.s.) and 1 drop of hydrochloric acid was heated in microwave at
150.degree. C. for 40 minutes. Still some starting material left.
Residue was heated again for 25 minutes at 150.degree. C. The
solvent was evaporated and residue was extracted (DCM/water). The
organic layers were collected, dried (MgSO.sub.4), filtered and
evaporated. The crude residue was used as such in the next
reaction, yielding intermediate (131).
c) Preparation of
##STR00132##
[0329] Intermediate (31) (0.0042 mol) was dissolved in TFA (15 ml).
The reaction mixture was stirred in microwave at 100.degree. C. for
30 minutes. The reaction mixture was evaporated. The residue was
extracted twice (ethyl acetate/NaHCO.sub.3). The collected organic
layers were dried (MgSO.sub.4), filtered and evaporated. The crude
residue was used as such in the next reaction, yielding
intermediate (132).
d) Preparation
##STR00133##
[0330] and
##STR00134##
[0331] A mixture of 4-bromo-2-fluoropyridine (0.635 g),
Pd.sub.2(dba).sub.3 (catalytic quantity), Xantphos (catalytic
quantity) and Cs.sub.2CO.sub.3 (1.5 g) in 1,4-dioxane (5 ml) was
degassed by applying alternating N.sub.2 atmosphere and vacuum.
Intermediate (132) in 1,4-dioxane (15 ml) was added under
N.sub.2-atmosphere. The reaction mixture was stirred at 100.degree.
C. for 2 hours. The reaction mixture was filtrated. After
extraction (DCM/water), the collected organic layers were dried
(MgSO.sub.4), filtered and the filtrate was evaporated. The residue
was purified by HPLC (HPLC method A). Two product fraction groups
were collected and their solvents were evaporated, yielding
intermediate (133) (trans; relative; mixture) and intermediate
(134) (cis; relative; mixture).
Example A.35
Preparation of
##STR00135##
[0333] Reaction under an inert Ar atmosphere. Sodium hydride (60%)
(1.81 g, 1.1 equiv.) was suspended in DMF (60 ml) and the
suspension was cooled to 0.degree. C. A solution of
4-iodo-1H-pyrazole (8 g, 0.04124 mol) in DMF (20 ml) was slowly
added to the cooled suspension and the reaction mixture was stirred
for 30 minutes at 0.degree. C. and then at room temperature for 30
minutes. The mixture was cooled again to 0.degree. C., and
potassium iodide (6.8 g, 1 equiv.) was added, followed by the
dropwise addition of 1-bromo-3-methoxypropane (9.47 g). The white
suspension was stirred for 30 minutes at 0.degree. C. and then at
room temperature for 3 hours. The mixture was cooled again to
0.degree. C. and was then quenched with water. The mixture was
diluted with ethyl acetate and the organic layer was separated. The
organic layer was washed with water and brine, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated in
vacuo (pale yellow oil). This oily residue was purified by column
chromatography over silica gel (eluent: hexane/ethyl acetate 3/1).
The desired fractions were collected and the solvent was
evaporated, yielding 9.064 g of intermediate (135).
Example A.36
a) Preparation of
##STR00136##
[0335] A mixture of intermediate (3) (0.05 mol) in acetic acid (400
ml) was stirred and refluxed for 3 hours. The reaction mixture was
cooled and then the solvent was evaporated. The residue was
extracted in DCM/water. The separated organic layer was dried
(MgSO.sub.4), filtered and the solvent was evaporated, yielding 6.5
g of intermediate (136).
b) Preparation of
##STR00137##
[0337] Reaction under inert Ar atmosphere.
[0338] Intermediate (136) (1 g, 0.00306 mol) was dissolved in TFA
(15 ml). The solution was stirred overnight at 100.degree. C. The
mixture was cooled and the deep black mixture was concentrated in
vacuo. The residue was taken up in ethyl acetate. The organic layer
was washed with NaHCO.sub.3 (saturated), water and brine, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated (green
residue). This green solid was dissolved in dioxane (15 ml) under
an inert atmosphere of Ar. 4-Bromo-2-fluoropyridine (0.00306 mol),
Cs.sub.2CO.sub.3 (1.5 g, 1.5 equiv.), Xantphos (0.09 g) and
Pd.sub.2(dba).sub.3 (0.08 g) were added. The reaction was degassed
for 15 minutes and was then heated for 30 minutes at 80.degree. C.
The cooled mixture was concentrated in vacuo and the resulting
thick brown oil was taken up in chloroform. The organic layer was
washed with NaHCO.sub.3 (saturated), water and brine, dried
(Na.sub.2SO.sub.4), filtered and the solvent was evaporated to
yield a brown solid. This solid was purified by column
chromatography over silica gel (eluent: hexane/ethyl acetate 1/1).
The desired fractions were collected and the solvent was
evaporated, yielding 0.642 g of intermediate (137).
c) Preparation of
##STR00138##
[0340] Reaction under inert Ar atmosphere.
[0341] Intermediate (137) (0.645 g, 0.00214 mol) was dissolved in
DMF. 2-(2-Bromoethyl)-1,3-dioxolane (0.002354 mol) was added and
subsequently potassium iodide (0.002354 mol) was added. The brown
mixture was cooled to 0.degree. C. and sodium hydride (60%) (0.129
g, 1.5 equiv.) was added dropwise. The brown reaction mixture was
stirred for 30 minutes at 0.degree. C., and then overnight at room
temperature. The mixture was quenched with water and the crude
product was extracted with ethyl acetate. The separated organic
layer was washed with water and brine, dried (Na.sub.2SO.sub.4),
filtered and the solvent was evaporated, to yield a pale green
solid. This solid was taken up in ethyl acetate, and hexane was
added. The precipitate (starting material) was filtered off and
washed with hexane. The filtrate was concentrated in vacuo. The
residue was worked up again, and a second amount of precipitate was
filtered off (starting material). The filtrate was evaporated and
the residue was purified by column chromatography over silica gel
(eluent: hexane/ethyl acetate 1/1). The desired fractions were
collected and the solvent was evaporated, yielding 0.302 g of
intermediate (138) (mixture of isomers).
Example A.37
a) Preparation of
##STR00139##
[0343] A mixture of
4-bromo-N.sup.1-[2-(1-pyrrolidinyl)ethyl]-1,2-benzenediamine
(0.0350 mol) in DCM (200 ml) was cooled to 0.degree. C.
2,2-Dimethylpropanoyl chloride (0.0350 mol) and then triethylamine
(5.8 ml) were added to the reaction mixture and stirred at room
temperature for 3 hours. The reaction mixture was washed with
water. The separated organic layer was dried (MgSO.sub.4), filtered
and the solvent was evaporated. The residue was suspended in DIPE,
the precipitate was filtered off and dried (vacuo, 40.degree. C.),
yielding 8g of intermediate (142).
b) Preparation of
##STR00140##
[0345] A mixture of intermediate (142) (0.0059 mol) in acetic acid
(30 ml) was heated for 20 minutes in a microwave at 150.degree. C.
The reaction mixture was cooled and the solvent was evaporated. The
residue was partitioned between ethyl acetate and water. This
mixture was neutralized with an aqueous NaHCO.sub.3 solution. The
separated organic layer was dried (MgSO.sub.4), filtered and the
solvent was evaporated, yielding 1.5 g of intermediate (143).
c) Preparation of
##STR00141##
[0347] A mixture of intermediate (143) (0.0005 mol),
4-methoxybenzenemethanethiol (0.001 mol), Pd.sub.2(dba).sub.3
(0.040 g) and Xantphos (0.040 g) in dioxane (10ml) was degassed.
N-ethyl-N-(1-methylethyl)-2-propanamine (0.001 mol) was added and
the reaction mixture was degassed again. The reaction mixture was
stirred at 100.degree. C. for 20 hours. The reaction mixture was
cooled and the solvent was evaporated. The residue was taken up in
DCM and water. The separated organic layer was dried (MgSO.sub.4),
filtered and the solvent was evaporated. The residue was purified
by column chromatography (eluent: DCM/methanol 99/1). The desired
product fractions were collected and the solvent was evaporated,
yielding 1.2 g of intermediate (144).
d) Preparation of
##STR00142##
[0349] A mixture of intermediate (144) (0.0028 mol) in TFA (15 ml)
was heated for 20 minutes in a microwave at 120.degree. C. The
solvent was evaporated. The residue was partitioned between ethyl
acetate and water. This mixture was neutralized with an aqueous
NaHCO.sub.3 solution. The separated organic layer was dried
(MgSO.sub.4), filtered and the solvent was evaporated, yielding
intermediate (145).
e) Preparation of
##STR00143##
[0351] A mixture of 4-bromo-2-fluoropyridine(0.0028 mol) and cesium
carbonate (1.7 g) in dioxane (10 ml) was degassed. Intermediate
(145) (theoretical maximum, crude) in dioxane (10 ml) was degassed
and added to the reaction mixture. Then Pd.sub.2(dba).sub.3
(0.110g) and Xantphos (0.150g) were added to the reaction mixture
and the reaction mixture was degassed. The reaction mixture was
stirred at 100.degree. C. for 1 hour. The reaction mixture was
cooled and the solvent was evaporated. The residue was taken up in
ethyl acetate and water. The separated organic layer was dried
(MgSO.sub.4), filtered and the solvent was evaporated. The residue
was purified by column chromatography (eluent: DCM/methanol 99/1).
The desired product fractions were collected and the solvent was
evaporated, yielding 0.450 g of residue. 0.100 g of residue was
purified by high performance liquid chromatography (standard
gradient elution with NH.sub.4HCO.sub.3 buffer). The desired
product fractions were collected and the solvent was evaporated.
The residue was suspended in DIPE, the precipitate was filtered off
and dried (vacuo, 40.degree. C.), yielding 0.029 g of intermediate
(146).
B. Synthesis of the Final Compounds
Example B.1
Preparation of
##STR00144##
[0352] and
##STR00145##
[0353] Cs.sub.2CO.sub.3 (1g) was added to a mixture of
5-bromo-2(1H)-pyridinone (0.870 g) and dioxane (6 ml). The
resulting mixture was degassed by alternating vacuum and nitrogen
atmosphere (3 cycles). Then a mixture of intermediate (9) (0.00157
mol) in dioxane (4 ml) was added, followed by Xantphos (0.056 g)
and Pd.sub.2(dba).sub.3 (0.044 g). The resulting reaction mixture
was degassed again by alternating vacuum and nitrogen atmosphere (3
cycles). The reaction mixture was shaken overnight in a closed
vessel at 100.degree. C. The mixture was then concentrated under a
stream of nitrogen at 65.degree. C. The residue was partitioned
between DCM and water and filtered over an Isolute HM-N.TM. filter
to remove the aqueous phase. The organic layer was concentrated
under a stream of nitrogen. The residue was purified by reversed
phase high-performance liquid chromatography. The product fractions
were collected and the solvent was evaporated, yielding
intermediate (23). A part of intermediate (23) (0.296 g) was
dissolved in chloroform (15 ml) and mCPBA (0.405 g; 2.2 equiv.) was
added. This mixture was shaken at room temperature overnight. The
organic layer was washed with NaOH (1 N) and the product was in the
water layer. Acetic acid was added to the water layer and an
extraction was performed with DCM. The organic layer was filtered
over an Isolute HM-N.TM. filter and the solvent was evaporated. The
residue was purified by reversed phase high-performance liquid
chromatograpy. The desired fractions were collected and the solvent
was evaporated, yielding compound (1) (mp. 251.degree. C.).
Example B.2
Preparation of
##STR00146##
[0354] and
##STR00147##
and
##STR00148##
[0355] Cs.sub.2CO.sub.3 (1g) was added to a mixture of
4-chloropyridine-N-oxide (0.650 g) in dioxane (6 ml). Then a
mixture of intermediate (9) (0.00156 mol) in dioxane (4 ml) was
added. The resulting reaction mixture was shaken overnight at
80.degree. C. The mixture was cooled and was then concentrated
under a stream of nitrogen. The residue was partitioned between DCM
and water and filtered over an Isolute HM-N.TM. filter to remove
the aqueous phase. The residue was purified by reversed phase
high-performance liquid chromatography. The product fractions were
collected and the solvent was evaporated, yielding intermediate
(24) (mp.: 186-187.degree. C.). A part of intermediate (24) (0.370
g) was dissolved in chloroform (15 ml) and mCPBA (0.430 g; max. 2
equiv.) was added. This mixture was shaken at room temperature
overnight. The organic layer was washed with NaOH (1 N), with water
and the filtrate was filtered over an Isolute HM-N.TM. filter and
concentrated under a stream of nitrogen. The residue was purified
by reversed phase HPLC. Two different product fractions were
collected and the solvent was evaporated, yielding 0.038 g compound
(2) and 0.280 g of compound (3) (mp. 203.degree. C.).
[0356] The heterocyclic reagent 4-chloropyridine-N-oxide can be
replaced by other heterocycles such as e.g. 3,6-dichloropyridazine
1-(6-chloro-3-pyridinyl)ethanone, 6-chloro-3-pyridinecarboxamide
for the preparation of other compounds of the invention.
Example B.3
Preparation of
##STR00149##
[0358] Cs.sub.2CO.sub.3 (0.0075 mol) was added to a mixture of
5-acetyl-2-bromopyridine (0.0065 mol) in dioxane (10 ml). The
mixture was degassed with nitrogen. Intermediate (9) (0.005 mol)
dissolved in dioxane (10 ml) was added to the reaction mixture
which was degassed again with nitrogen. Xantphos (0.115 g) and then
Pd.sub.2(dba).sub.3 (0.090 g) were added to the reaction mixture
and degassed again with nitrogen. The reaction mixture was stirred
overnight at 100.degree. C. Water (150 ml) was added. This mixture
was extracted twice with DCM (100 ml). The combined organic layers
were dried, filtered and the solvent was evaporated. The residue
was dissolved in chloroform (4g) and then mCPBA (100 ml) was added.
The reaction mixture was stirred overnight at room temperature. The
reaction mixture was washed first twice with NaOH aqueous solution
(1N, 100 ml), and then washed with water (100 ml). The separated
organic layer was dried, filtered and the solvent was evaporated.
The residue was purified by column chromatography over silica gel
(eluent: CH.sub.2Cl.sub.2/(CH.sub.3OH/NH.sub.3) from 100/0 to
97/3). The product fractions were collected and the solvent was
evaporated, yielding compound (4).
Example B.4
Preparation of
##STR00150##
[0360] A mixture of intermediate (25) (0.002 mol) and mCPBA (0.005
mol) in chloroform (50 ml) was stirred at room temperature for 30
minutes. Then water was added. The separated organic layer was
dried, filtered and the solvent was evaporated. The residue was
purified by reversed phase chromatography. The desired fractions
were collected and the solvent was evaporated, yielding 0.30 g of
compound (6).
Example B.5
Preparation of
##STR00151##
[0362] A mixture of compound (18) (0.00021 mol) and NH.sub.3 in
ethanol (5 ml) was stirred for two days at 120.degree. C. The
reaction mixture was extracted with DCM. The organic layer was
removed, evaporated and the residue was purified by column
chromatography over silica gel (eluent: CH.sub.2Cl.sub.2/CH.sub.3OH
gradient from 100/0 to 96/4). The product fractions were collected
and the solvent was evaporated, yielding 0.051 g of compound
(19).
Example B.6
Preparation of
##STR00152##
[0364] 3-Chloro-6-methoxypyridazine (0.006 mol) was dissolved in
1,4-dioxane (10 ml). Cs.sub.2CO.sub.3 (2.1 g) was added and the
mixture was degassed. A degassed solution of intermediate (19)
(0.003 mol) in 1,4-dioxane (10 ml) was added. Pd.sub.2(dba).sub.3
(0.080 g) was added and the mixture was degassed. Xantphos (0.095
g) was added and the mixture was degassed. The reaction mixture was
stirred for 20 hours at 100.degree. C., then cooled and the solvent
was evaporated. The residue was partitioned between ethylacetate
and water. The organic layer was separated, dried, filtered and the
solvent was evaporated. The residue was stirred in chloroform (30
ml). This mixture was treated with mCPBA (2.1 g). The reaction
mixture was stirred for one hour at room temperature, then it was
washed with 1 N NaOH (2.times.). The organic layer was separated,
dried, filtered and the solvent was evaporated. The residue was
purified by column chromatography over silica gel (eluent:
CH.sub.2Cl.sub.2/CH.sub.3OH 99/1). The product fractions were
collected and the solvent was evaporated. The residue was purified
by reversed-phase HPLC (gradient elution with NH.sub.4HCO.sub.3
buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN). The product
fractions were collected and the solvent was evaporated. Methanol
was added and evaporated again. The residue was dissolved in
diethyl ether and converted into the hydrochloric acid salt (1:1)
with HCl/diethyl ether. The resulting precipitate was filtered off
and dried, yielding 0.034 g of compound (26).
Example B.7
Preparation of
##STR00153##
[0365] and
##STR00154##
[0366] Cs.sub.2CO.sub.3 (1g) was added to a mixture of
3-iodopyridine (1g) and dioxane (6 ml). The resulting mixture was
degassed by alternating vacuum and N.sub.2 atmosphere (3 cycles).
Then a mixture of intermediate (9) (max. 0.00157 mol) in dioxane (4
ml) was added, followed by Xantphos (0.056 g) and
Pd.sub.2(dba).sub.3 (0.044 g). The resulting reaction mixture was
degassed again by alternating vacuum and N.sub.2 atmosphere (3
cycles). The reaction mixture was shaken overnight in a closed
vessel at 100.degree. C. The mixture was concentrated under a
stream of N.sub.2 at 65.degree. C. The residue was partitioned
between CH.sub.2Cl.sub.2 and H.sub.2O and filtered over an ISOLUTE
HM-N filter to remove the aqueous phase. The organic layer was
concentrated under a stream of N.sub.2. The residue was purified by
reversed phase high-performance liquid chromatography. The product
fractions were collected and the solvent was evaporated, yielding
0.240 g of intermediate (140). A part of intermediate (140) (0.215
g) was dissolved in chloroform (15 ml) and mCPBA (2.5 equiv.) was
added. This mixture was shaken at room temperature overnight. The
organic layer was washed 2.times. with NaOH (1 N, 5 ml), with
H.sub.2O (5 ml) and the organic layer was filtered over an ISOLUTE
HM-N filter. The filtrate was concentrated under a stream of
N.sub.2. The residue was purified by reversed-phase HPLC. The
desired product fraction was collected and the solvent was
evaporated, yielding 0.028 g of compound (34).
Example B.8
a) Preparation of
##STR00155##
[0368] A mixture of compound (35) (0.0021 mol) and a solution of
lithium hydroxide in water (1N) (10 ml) in THF (40 ml) was stirred
at room temperature overnight. The reaction mixture was neutralized
to pH=7 with 1N HCl aqueous solution. The solvent was evaporated.
The residue was purified by reversed-phase HPLC (gradient elution
with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and worked-up, yielding 0.7 g of compound (46).
b) Preparation of
##STR00156##
[0370] Compound (46) (0.00044 mol) was added to a mixture of
triethylamine (0.00066 mol) in chloroform (10 ml).
2-Methoxy-ethanamine (0.0006 mol) was added and was shaken
overnight at room temperature. DCM (100 ml) was added. This mixture
was washed 2 times with water (100 ml). The separated organic layer
was dried (MgSO.sub.4), filtered and the solvent was evaporated.
The residue was purified by reversed-phase HPLC (gradient elution
with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and worked-up. The residue was triturated under acetonitril. The
precipitate was filtered off, yielding 0.105 g compound (37) (mp.
206.degree. C. to 207.degree. C.).
[0371] The following compound was prepared in a similar way using
pyrrolidine instead of 2-methoxy-ethanamine as reagent
##STR00157##
Example B.9
Preparation of
##STR00158##
[0373] NaBH.sub.4 (0.003 mol) was added to a mixture of compound
(40) (0.001 mol) in a mixture of methanol/ethanol(50/50) (20 ml),
stirred at room temperature under N.sub.2 atmosphere. The reaction
mixture was stirred overnight at room temperature. The reaction
mixture was concentrated. DCM (100 ml) was added. Water (50 ml) was
added. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvent was evaporated. The residue was
crystallized from DIPE/2-propanol. The precipitate was filtered
off, washed and dried, yielding 0.290 g of compound (41).
Example B.10
a) Preparation of
##STR00159##
[0375] NaBH.sub.4 (0.015 mol) was added to a mixture of compound
(4) (0.0011 mol) in ethanol (30 ml) and stirred at room
temperature. DCM (30 ml) was added and stirred for 2 hours at room
temperature. The reaction mixture was quenched with HCl 1N aqueous
solution (10 ml). Water (100 ml), NH.sub.4OH aqueous solution (20
ml) and DCM (100 ml) were added to the reaction mixture. The
mixture was separated into aqueous layer and organic layer. The
aqueous layer was re-extracted with DCM (100 ml). The organic
layers were combined and washed with brine. The separated organic
layer was dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by column chromatography over
silica gel (eluent: DCM/(CH.sub.3OH/NH.sub.3) from 100/0 to 94/6).
The product fractions were collected and the solvent was
evaporated, yielding 0.36 g of product. This product (0.36 g) was
triturated under DIPE/CH.sub.3CN. The precipitate was filtered off,
yielding compound (42) (mp. 177.degree. C. to 179.degree. C.).
##STR00160##
b) Preparation of
[0376] Sodium hydride (60%) (0.00125 mol) was added to a mixture of
compound (42) (0.000656 mol) in THF (15 ml) and was stirred for 20
minutes at room temperature. Iodomethane (0.0014 mol) was added and
stirred at room temperature overnight. Sodium hydride (60%)
(0.00125 mol) was added again and stirred for 20 minutes at room
temperature. Then iodomethane (0.0014 mol) was added again and
stirred over the weekend at 40.degree. C. Water (100 ml) and DCM
(100 ml) were added. After extraction, the separated organic layer
was dried (MgSO.sub.4), filtered and the solvent was evaporated.
The residue was purified by reversed-phase HPLC (gradient elution
with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and the solvent was evaporated. The residue was re-crystallized
from DIPE/few drops of CH.sub.3CN and the precipitate was filtered
off, yielding 0.110 g of compound (49) (mp. 140.degree. C.).
Example B.11
Preparation of
##STR00161##
[0377] and
##STR00162##
[0378] Cs.sub.2CO.sub.3 (0.015 mol) was added to a mixture of
5-bromo-3-pyridinecarbonitrile (0.013 mol) in dioxane (20 ml). The
mixture was degassed with N.sub.2. Intermediate (9) (0.01 mol) in
dioxane (20 ml) was added to the reaction mixture and degassed
again with N.sub.2. Xantphos (0.230 g) and then Pd.sub.2(dba).sub.3
(0.180 g) were added to the reaction mixture and degassed again
with N.sub.2. The reaction mixture was stirred overnight at
100.degree. C. Water (150 ml) was added. This mixture was extracted
2 times with DCM (100 ml). The combined organic layers were dried
(MgSO.sub.4), filtered and the solvent was evaporated. The residue
was purified by combiflash column chromatography over silica gel
(eluent: DCM/(CH.sub.3OH/NH.sub.3) from 100/0 to 98/2). The product
fractions were collected and the solvent was evaporated, yielding
2g of intermediate (141). Intermediate (141) (2g) was dissolved in
chloroform (3g) and then 3-chlorobenzene-carboperoxoic acid (50 ml)
was added. The reaction mixture was stirred for 2 hours at room
temperature. The reaction mixture was washed first 2 times with
NaOH 1N aqueous solution (200 ml), and then washed with brine (200
ml). The separated organic layer was dried (MgSO.sub.4), filtered
and the solvent was evaporated. The residue was purified by
combiflash column chromatography over silica gel (eluent:
DCM/(CH.sub.3OH/NH.sub.3) from 100/0 to 98/2). The product
fractions were collected and the solvent was evaporated. The
residue was re-crystallized from 2-propanol/CH.sub.3CN and the
precipitate was filtered off, yielding 0.9 g of compound (43) (mp.
240.degree. C.).
Example B.12
Preparation of
##STR00163##
[0380] Compound (43) (0.0006 mol) in sulfuric acid (4 ml) was
stirred at 30.degree. C.-40.degree. C. for 5 hours. The reaction
mixture was poured out on ice (100 ml). This mixture was extracted
4 times with DCM/CH.sub.3OH (100 ml). The combined organic layers
were dried (MgSO.sub.4), filtered and the solvent was evaporated.
The residue was re-crystallized from DCM and the precipitate was
filtered off, yielding 0.170 g of compound (44) (mp. 259.degree.
C.).
Example B.13
Preparation of
##STR00164##
[0382] A mixture of compound (4) (0.0032 mol), 1,2-ethanediol (1
ml) and 4-methylbenzene-sulfonic acid (0.6 g) in toluene (70 ml)
was stirred at reflux with a water separator. The reaction mixture
washed with NaHCO.sub.3 saturated aqueous solution. The separated
organic layer was dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by reversed-phase HPLC
(gradient elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and the solvent was evaporated. The residue was re-crystallized
from DIPE/CH.sub.3CN and the precipitate was filtered off, yielding
0.606 g of compound (45) (mp. 191.degree. C.).
Example B.14
Preparation of
##STR00165##
[0384] A mixture of compound (6) (0.15 g, 0.0003 mol) and
2-propanol (10 ml) was heated.
[0385] A mixture of 2-propanol and HCl (6N) (1 ml) was added. Then
the mixture was cooled. The precipitate was filtered off, washed
and dried, yielding 0.060 g of compound (47.
Example B.15a
Preparation of
##STR00166##
[0387] A mixture of intermediate (33) (0.013 mol) and
3-chlorobenzenecarboperoxoic acid (0.030 mol) in chloroform (150
ml) was stirred at room temperature for 30 minutes. Then water was
added. The separated organic layer was dried (MgSO.sub.4), filtered
and the solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: DCM/CH.sub.3OH from 100/0
to 98.5/1.5). The product fractions were collected and the solvent
was evaporated. The residue was solidified in DIPE, then filtered
off, washed and dried, y ielding 3.3 g of compound (170).
Example B.15b
Preparation of
##STR00167##
[0389] A mixture of compound (170) (0.0045 mol), hydroxylamine
(0.009 mol) and NaHCO.sub.3 (0.009 mol) in 2-propanol (40 ml) was
stirred for 5 hours at 60.degree. C., then cooled and the solvent
was evaporated. The residue was taken up into DCM. The organic
solution was washed with water, dried (MgSO.sub.4), filtered and
the solvent was evaporated, yielding 1.36 g of compound (171).
Example B.15c
Preparation of
##STR00168##
[0391] A mixture of compound (171) (0.0011 mol) and
trifluoro[1,1'-oxybis[ethane]]boron (0.200 ml) in trimethoxymethane
(2 ml) was stirred for 2 hours at 80.degree. C. The reaction
mixture was cooled and the solvent was evaporated. The residue was
taken up into DCM and the organic solution was washed with water,
then dried (MgSO.sub.4), filtered and the solvent was evaporated.
The residue was crystallized from DIPE with a small amount of
2-propanol. The precipitate was filtered off, washed and dried,
yielding 0.325 g of compound (48).
Example B.16
Preparation of
##STR00169##
[0393] A mixture of compound (40) (0.0011 mol) in diethyl ether (10
ml) and THF (5 ml) was stirred at room temperature under N.sub.2
atmosphere. A solution of bromomethyl-magnesium in diethyl ether
(3M) (0.0030 mol) was added dropwise. The reaction mixture was
stirred overnight. Water was added carefully. More diethyl ether
was added. The organic layer was separated, dried (MgSO.sub.4),
filtered and the solvent was evaporated. The residue was purified
by reversed-phase HPLC (gradient elution with NH.sub.4HCO.sub.3
buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN). The product
fractions were collected and the solvent was evaporated. Methanol
was added and co-evaporated, yielding 0.445 g of compound (53).
Example B.17
Preparation of
##STR00170##
[0395] Compound (62) (0.00021 mol) in 2-propanol (5 ml) was stirred
at room temperature. Then methanesulfonyl chloride (0.00031 mol)
was added. The reaction mixture was warmed up and then cooled. The
precipitate was filtered off, washed and dried, yielding 0.077 g of
compound (64).
Example B.18
Preparation of
##STR00171##
[0396] and
##STR00172##
[0397] A mixture of compound (69) (0.00025 mol) and a solution of
sodium methylate in methanol(30%) (0.5 ml) in methanol (10 ml) was
stirred overnight at room temperature. The solvent was evaporated.
The residue was purified by reversed-phase HPLC. Two product
fraction groups were collected and worked-up, yielding 0.015 g of
compound (77) and 0.022 g of compound (78).
Example B.19
Preparation of
##STR00173##
[0398] and
##STR00174##
[0399] A mixture of intermediate (44) (0.00133 mol) and
3-chlorobenzene-carboperoxoic acid (0.0027 mol) in chloroform (15
ml) was shaken overnight at room temperature. The mixture was
washed with 1 N NaOH (2.times.15 ml), once with water (15 ml). The
organic phase was filtered through an Isolute HM-N filter, and the
filtrate's solvent was evaporated under a stream of N.sub.2. The
residue was purified by reversed-phase HPLC. Two product fractions
were collected and their solvent was evaporated. Each fraction was
crystallized from DIPE/2-propanol, filtered off and dried, yielding
0.155 g of compound (85) and 0.161 g of compound (84).
Example B.20
Preparation of
##STR00175##
[0400] and
##STR00176##
and
##STR00177##
[0401] 3-Chlorobenzenecarboperoxoic acid (0.007 mol) was added
portionwise to intermediate (45) (0.00348 mol) in chloroform (20
ml). The reaction mixture was shaken overnight at room temperature.
The organic mixture was washed with 1 N NaOH (2.times.20 ml), once
with water (20 ml), then filtered through an Isolute HM-N filter,
and the filtrate's solvent was evaporated under a stream of
N.sub.2. The residue was purified by reversed-phase HPLC. Different
product fractions were collected and their solvent was evaporated.
Each residue was crystallized from DIPE/2-propanol. Each
precipitate was filtered off and dried, yielding 0.242 g of
compound (86); 0.213 g of compound (87) and 0.1 g of compound
(88).
Example B.21
Preparation of
##STR00178##
[0403] A mixture of intermediate (46) (0.0043 mol) and
3-chlorobenzene-carboperoxoic acid (0.005 mol) in chloroform (80
ml) was shaken for one hour at room temperature. More
3-chlorobenzenecarboperoxoic acid (0.005 mol) was added and the
reaction mixture was shaken overnight at room temperature. The
mixture was washed with 1 N NaOH (2.times.75 ml), once with water
(75 ml). The organic phase was dried (MgSO.sub.4), filtered and the
solvent was evaporated. The residue was purified by column
chromatography over silica gel (eluent: DCM/(CH.sub.3OH/NH.sub.3)
97/3). The product fractions was collected and the solvent was
evaporated. The residue (1.35 g) was purified further by
reversed-phase HPLC. The desired fraction groups were collected and
the solvent was evaporated. The residue of the desired product was
crystallized from 2-propanol/DIPE, yielding 0.646 g of compound
(89).
Example B.22
Preparation of
##STR00179##
[0405] A mixture of intermediate (30) (0.77 g, 0.0019 mol), mCPBA
(70%) (1.17 g, 0.0047 mol) and chloroform (40 ml) was stirred at
room temperature for 1 hour. Chloroform (100 ml) was added and the
mixture was washed with a NaOH solution (1 N; 2.times.100 ml). The
organic layer was dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by column chromatography over
silica gel (eluent: DCM/CH.sub.3OH(NH.sub.3) from 100/0 till 97/3.
The desired fractions were collected and the solvent was
evaporated. The residue was dissolved in 2-propanol (approx. 50 ml)
and methylsulfonic acid (0.12 g was added). The methylsulfonate
salt crystallized from this solution. The product was filtered off,
washed with 2-propanol/DIPE and dried (in vacuo), yielding 0.63 g
of compound (93).
Example B.23
a) Preparation of
##STR00180##
[0407] A mixture of compound (11) (0.0036 mol, 1.6 g) in
hydrochloric acid was stirred and refluxed for 1 hour. The reaction
mixture was cooled and DCM was added. The organic layer was
separated, dried, filtered and the solvent evaporated, yielding
1.108 g of compound (94).
b) Preparation of
##STR00181##
[0409] A mixture of compound (94) (0.0005 mol, 0.200 g, 1 equiv.)
and 1,1-dimethoxy-N,N-dimethylmethanamine (0.100 ml, 1.5 equiv.) in
DMF (1 ml) was stirred and refluxed until reaction was complete.
Ice was added. Residue 1 precipitated from the mixture. The rest of
the mixture was extracted with DCM. Water was added. The organic
layer was separated, dried, filtered, and the solvent was
evaporated, yielding residue 2. Residue 1 and 2 were combined and
the mixture was triturated under 2-propanol. The precipitate was
filtered off and dried in vacuo, yielding 0.125 g of compound
(100).
Example B.24
Preparation of
##STR00182##
[0411] A mixture of intermediate (54) (0.00122 mol) and
3-chlorobenzenecarboperoxoic acid (0.0027 mol) in chloroform (15
ml) was shaken for 3 hours at room temperature. More
3-chlorobenzenecarboperoxoic acid (0.32 g) was added and the
reaction mixture was shaken overnight at room temperature. The
mixture was washed with 1 N NaOH (2.times.15 ml), once with water
(15 ml). Then the organic phase was filtered through an Isolute
HM-N filter, and the filtrate's solvent was evaporated under a
stream of N.sub.2. The residue was purified by reversed-phase HPLC.
The product fraction was collected and worked-up, yielding 0.100 g
of compound (95).
Example B.25
Preparation of
##STR00183##
[0413] A mixture of intermediate (56) (0.00121 mol) and
3-chlorobenzenecarboperoxoic acid (0.00242 mol) in chloroform (18
ml) was shaken for 2 hours at room temperature. The mixture was
washed with 1 N NaOH (2.times.15 ml), once with water (15 ml), then
filtered through an Isolute HM-N filter, and the filtrate's solvent
was evaporated under a stream of N.sub.2. The residue was purified
by Combiflash flash column chromatography over silica gel (eluent:
DCM/(CH.sub.3OH/NH.sub.3) from 100/0 to 96/4). The desired product
fraction was collected and the solvent was evaporated, yielding
0.110 g of compound (101).
Example B.26
Preparation of
##STR00184##
[0415] 3-Chlorobenzenecarboperoxoic acid (1 g) was added in 2
portions to a solution of intermediate (63) (0.001 mol) in
chloroform (40 ml) at room temperature. The reaction mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was washed with water/NaOH. The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The residue was purified
over a filter with silica gel using DCM/CH.sub.3OH (7N NH.sub.3)
from 100/0 to 96/4 as eluent. The product fractions were collected
and evaporated. The product was crystallized from DIPE and
2-propanol. The solid was filtered off, washed and dried, yielding
0.24 g of compound (159).
Example B.27
Preparation of
##STR00185##
[0417] 3-Chlorobenzenecarboperoxoic acid (0.2 g) was added in 2
portions to a solution of intermediate (64) (0.003 mol) in
chloroform (20 ml) at room temperature. The reaction mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was washed with water/NaOH. The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The residue was purified
over a column with silica gel using DCM/CH.sub.3OH (7N NH.sub.3)
from 100/0 to 98/2 as eluent. The product fractions were collected
and evaporated. The residue was crystallized from 2-propanol and
some DIPE. The solid was filtered off, washed and dried, yielding
0.058 g of compound (168).
Example B.28
Preparation of
##STR00186##
[0419] A mixture of intermediate (67) (0.0007 mol),
3-chlorobenzenecarboperoxoic acid (36 g) and chloroform (20 ml) was
shaken at room temperature for 20 minutes. The reaction mixture was
washed with 2.times.15 ml 1N aq. NaOH, 1.times.15 ml water, and
filtered over an isolute HM-N filter. The solvent was removed under
a stream of N.sub.2 at 50.degree. C., and the residue crystallized
from DIPE, yielding 0.2 g of compound (156).
Example B.29
Preparation of
##STR00187##
[0421] Intermediate (71) (0.0023 mol) was dissolved in chloroform
(40 ml) at room temperature. 3-Chlorobenzenecarboperoxoic acid
(0.567 g) was added slowly (exothermic reaction) and the mixture
was stirred for 30 minutes. The reaction mixture was extracted
twice with saturated NaHCO.sub.3 and once with 1N NaOH. The organic
layers were washed with water and dried (MgSO.sub.4). The residue
was purified by HPLC (HPLC method A). The desired fractions were
collected and the solvent was evaporated, yielding compound
(163).
Example B.30
a) Preparation of
##STR00188##
[0423] A mixture of compound (51) (0.0003 mol), Raney nickel (0.02
g) and NH.sub.3 in methanol (50 ml) was catalytic hydrogenated
under hydrogen atmosphere at 14.degree. C. After uptake H.sub.2 (2
equivalents) the reaction mixture was filtered over dicalite, and
concentrated. (During evaporation the reaction mixture turns dark
green,). The residue was purified by reversed phase HPLC (gradient
elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN), yielding 115 mg of compound
(116).
b) Preparation of
##STR00189##
[0425] A mixture of compound (116) (0.0002 mol), acetic acid
1,1'-anhydride (0.0003 mol) and DCM (10 ml) was shaken at room
temperature for 2 hours. The organic layer was washed with
2.times.15 ml sat. aq. NaHCO.sub.3 solution and 1.times. with 15 ml
water. The mixture was filtered over an isolute HM-N filter. The
filtrate was dried under stream of nitrogen at 60.degree. C. The
residue was crystallized from DIPE/2-propanol, yielding 71 mg of
compound (117).
Example B.31
Preparation of
##STR00190##
[0426] and
##STR00191##
[0427] A solution of intermediate (80) (0.07 g, 0.000182 mol) in
chloroform (ethanol free) (3 ml) was cooled to 0.degree. C. mCPBA
(70%) (0.135 g, 0.000546 mol) was added. The mixture was stirred
for 30 minutes at 0.degree. C. and then for 2 hours at room
temperature. An extra amount of mCPBA (70%) (3 equiv.) was added
and the mixture was stirred again for 90 minutes. Then the mixture
was diluted with chloroform and an extraction procedure was done
with NaOH (1 N); water and NaCl. After the extraction, two products
(A and B) were obtained.
Product A: The separated organic layer was evaporated, yielding
0.040 g of crude residue A. The crude was purified by column
chromatography over silica gel. The desired fractions were
collected and the solvent was evaporated, yielding 0.028 g of
compound (137). Product B: The aqueous layer (NaOH) obtained after
the extraction was also evaporated. The residue was triturated with
chloroform in an ultra-sonic bath for 15 minutes, filtered and
concentrated, yielding 0.040 g of compound (118).
Example B.32
Preparation of
##STR00192##
[0429] A mixture of intermediate (91) (0.00024 mol, crude) in
acetic acid (3 ml) was heated for 20 minutes at 150.degree. C. in a
microwave oven. Hydrochloric acid (2 drops) was added and the
reaction mixture was heated for 2 hours at 150.degree. C.
(microwave oven). Upon cooling, the solvent was evaporated. The
residue was partitioned between DCM and an aqueous NaHCO.sub.3
solution. The organic layer was separated, dried, filtered and the
solvent evaporated. The residue was separated and purified by
reversed-phase HPLC (gradient elution with (NH.sub.4OAc 0.5% in
water/CH.sub.3CN 90/10)/CH.sub.3OH/CH.sub.3CN). The desired product
fraction was collected and worked-up, yielding 0.006 g of compound
(122).
Example B.33
a) Preparation of
##STR00193##
[0431] A reaction mixture of compound (25) (0.0007 mol) and
N-(2-aminoethyl)acetamide (0.0022 mol) in dioxane (15 ml) was
stirred at 110.degree. C. for 20 hours. The reaction mixture was
cooled and the solvent was evaporated. The residue was taken up in
DCM and water. The separated organic layer was dried (MgSO.sub.4),
filtered and the solvent was evaporated. The residue was purified
by column chromatography (eluent: DCM/CH.sub.3OH from 100/0 to
98/2). The product fractions were collected and the solvent was
evaporated. The residue was suspended in DIPE/ drop CH.sub.3CN. The
precipitate was filtered off and dried (vacuo, 50.degree. C.),
yielding 0.100 g of compound (123).
[0432] Compound (126) can be prepared in a similar way as compound
(123) starting from compound (25) and using 3-methoxy-1-propanamine
instead of N-(2-aminoethyl)-acetamide
##STR00194##
b) Preparation of
##STR00195##
[0434] Reaction under N.sub.2. Sodium hydride (60%) (0.001 mol) was
added to compound (25) (0.0007 mol) in THF (5 ml) and stirred for
15 minutes at 40.degree. C. Then 4-morpholine-propanol (0.001 mol)
in THF (5 ml) was added. The reaction mixture was stirred at
50.degree. C. for 20 hours. The reaction mixture was cooled and the
solvent was evaporated. The residue was taken up in DCM/water. The
organic layer was separated, dried (MgSO.sub.4), filtered and the
filtrate's solvent was evaporated. The residue was purified by
reversed-phase HPLC (gradient elution with NH.sub.4HCO.sub.3 buffer
(0.25% in water)/CH.sub.3OH/CH.sub.3CN). The product fractions were
collected and the solvent was evaporated. This residue was stirred
at 0.degree. C. in ethyl acetate and HCl in 2-propanol. The
precipitate was filtered off and dried (vacuo, 60.degree. C.),
yielding 0.044 g of compound (135).
c) Preparation of
##STR00196##
[0436] A mixture of compound (25) (0.0016 mol), 1,3-propanediol
(0.005 mol), 2-methyl-2-propanol, potassium salt in THF (1M) (2 ml)
and dioxane (10 ml) was stirred at 80.degree. C. for 2 hours. The
reaction mixture was cooled. Water (100 ml) was added and the
mixture was extracted with 5.times.80 ml DCM. The organic layer was
dried (MgSO.sub.4), and concentrated, yielding 0.7 g of residue.
The residue was purified by reversed-phase HPLC (HPLC method B) and
worked-up (crystallized from DIPE), yielding 0.170 g of compound
(152).
d) Preparation of
##STR00197##
[0438] A mixture of (3-hydroxypropyl)carbamic acid,
1,1-dimethylethyl ester (0.0033.mol) and sodium hydride in mineral
oil (60%) (0.0033 mol) in dioxane (10 ml) was stirred at 60.degree.
C. for 30 minutes. Compound (25) (0.00162 mol) was added and the
reaction mixture was stirred overnight at 100.degree. C. The
reaction mixture was cooled. Water (100 ml) was added. This mixture
was extracted with DCM (2.times.100 ml). The separated organic
layer was dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was purified by reversed-phase HPLC
(gradient elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
and the solvent was evaporated, yielding 0.225 g of compound
(130).
[0439] Other final compounds can be prepared in a similar way as
compound (130) by replacing (3-hydroxypropyl)carbamic acid,
1,1-dimethylethyl ester with 3-(dimethylamino)-1-propanol,
3-methoxy-1-propanol, or 2-methoxyethanol.
e) Preparation of
##STR00198##
[0441] A mixture of compound (130) (0.00036 mol) and TFA (5 ml) in
DCM (5 ml) was stirred at room temperature for 20 minutes. The
solvents were removed under a stream of N.sub.2. The residue was
dissolved in DCM (12 ml), and washed with 1 N aq. NaOH (10 ml) and
water (10 ml). The organic phase was filtered over an Isolute HM-N
filter and the solvent was evaporated under a stream of N.sub.2,
yielding 0.176g of compound (131).
f) Preparation of
##STR00199##
[0443] A mixture of compound (131) (0.003 mol), acetic acid
1,1'-anhydride (0.067 g) and DCM (10 ml) was shaken at room
temperature for 3 hours. The reaction mixture was washed with
2.times.10 ml 1N aq. NaOH, 1.times.10 ml water, and filtered over
an isolute HM-N filter. The filtrate was concentrated under a
stream of N.sub.2 and crystallized as HCl salt in diethyl ether,
yielding 14g of compound (132).
Example B.34
Preparation of
##STR00200##
[0444] and
##STR00201##
[0445] Intermediate (95) (0.233 g, 0.000528 mol) was dissolved in
chloroform. 3-Choro-benzenecarboperoxoic acid (0.260 g, 2 equiv.)
was added. The mixture was partitioned between DCM and an aqueous
NaHCO.sub.3 solution. The organic layer was separated, dried,
filtered and the solvent evaporated. The residue (crude, 0.0005
mol) was dissolved in acetic acid (15 ml). Fe powder (0.215 g) was
added. The reaction mixture was stirred for 2 hours at room
temperature. The solvent was evaporated. The residue was
partitioned between DCM and an aqueous NaHCO.sub.3 solution. The
organic layer was separated, dried, filtered and the solvent
evaporated. The residue was separated and purified by HPLC. Two
product fraction groups were collected and worked-up, yielding
0.080 g of compound (124) and 0.030 g of compound (125).
Example B.35
a) Preparation of
##STR00202##
[0447] 3-Chorobenzenecarboperoxoic acid (0.001 mol) was added in 2
portions to a solution of intermediate (109) (0.003 mol) in
chloroform (20 ml) at room temperature. The reaction mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was washed with water/NaOH. The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The residue was purified
over a filter with silica gel using DCM/CH.sub.3OH (7N NH.sub.3)
from 100/0 to 99/1 as eluent. The product fractions were collected
and evaporated. The product was solidified from DIPE. The solid was
filtered off, washed and dried, yielding 0.12 g of compound (146)
(1,4-TRANS; relative; mixture).
b) Preparation of
##STR00203##
[0449] To a mixture of 4 .ANG. molecular sieves (0.2 g) in DCM
(dry) (3 ml) and Pyridine, trioxochlorochromate (VI) under N.sub.2
atm., was added compound (146) (0.0002 mol) in DCM(1 ml). The
reaction mixture was stirred at room temperature for 2 hours. The
reaction mixture was poured over a filter with dicalite. The
filtrate was concentrated. The residue was used crude, yielding
compound (134).
c) Preparation of
##STR00204##
[0451] Bromomethylmagnesium in diethyl ether (3.0 M) (0.2 ml) was
added to diethyl ether (3 ml). The reaction mixture was cooled to
-60.degree. C. Compound (134) (0.0002 mol) in THF (1 ml) was added
and the reaction mixture was allowed to reach room temperature. The
solvent was evaporated, and the residue was taken into DCM/water.
The organic layer was separated, filtered over an Isolute filter
and the filtrate's solvent was evaporated. The residue was purified
by reversed-phase HPLC purification (gradient elution with
NH.sub.4HCO.sub.3 buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN).
The product fractions were collected and the solvent was
evaporated. CH.sub.3OH was added and then evaporated. The residue
was dried under vacuum at 50.degree. C., yielding 8 mg of compound
(153) (1,4-CIS; relative; mixture).
Example B.36
Preparation of
##STR00205##
[0453] 3-Chorobenzenecarboperoxoic acid (0.003 mol) was added in 2
portions to a solution of intermediate (112) (0.009 mol) in
chloroform (15 ml) at room temperature. The reaction mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was washed with water/NaOH. The organic layer was dried (MgSO4),
filtered and evaporated. The residue was purified by column
chromatography using DCM/CH.sub.3OH:NH.sub.3 (100% to 98%/2%) as
eluent. The product fractions were collected and evaporated. The
residue was further purified by reversed-phase HPLC (gradient
elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were collected
, evaporated and co-evaporated with CH.sub.3CN. The residue was
solidified in diethyl ether by adding 1 ml of a HCl/ether solution
(1M). The solid was filtered off, washed and dried, yielding 0.15g
of compound (136).
Example B.37
Preparation of
##STR00206##
[0455] 3-Chorobenzenecarboperoxoic acid (0.0009 mol) was added in 2
portions to a solution of intermediate (114) (0.0003 mol) in
chloroform (10 ml) at room temperature. The reaction mixture was
stirred at room temperature for 30 minutes. The reaction mixture
was washed with water/NaOH. The organic layer was
dried(MgSO.sub.4), filtered and evaporated. The residue was taken
up in acetic acid (100%) (5 ml) and Fe powder (0.1 g). This mixture
was stirred at 60.degree. C. for 1 hour. The residue was purified
by column chromatography using DCM/CH.sub.3OH:NH.sub.3 (100% to
98%/2%) as eluent. The product fractions were collected and
evaporated. The residue was further purified by reversed-phase HPLC
(gradient elution with NH.sub.4HCO.sub.3 buffer (0.25% in
water)/CH.sub.3OH/CH.sub.3CN). The product fractions were
collected, concentrated and then extracted with DCM. The organic
layer was dried (MgSO.sub.4), filtered and evaporated. The residue
was crystallized from DIPE, 2-propanol and HCl/ether 1M solution
(0.5 ml). The solid was filtered off, washed and dried, yielding
0.04 g of compound (1 38).
Example B.38
a) Preparation of
##STR00207##
[0457] A mixture of intermediate (117) (0.0005 mol) in chloroform
(20 ml) was cooled to 0.degree. C. 3-Chorobenzenecarboperoxoic acid
(0.210 g) was added and the reaction mixture and stirred for 2
hours. The separated organic layer was washed with NaOH aqueous
solution (1M), dried (MgSO.sub.4), filtered and the solvent was
evaporated. The residue was added to acetic acid (6 ml). Then Fe
powder (0.280 g) was added. The mixture was stirred at 60.degree.
C. for 90 minutes. The mixture was cooled and the solvent was
evaporated. The residue was partitioned between DCM and water. This
mixture was alkalized with NaHCO.sub.3. The separated organic layer
was dried (MgSO.sub.4), filtered and the solvent was evaporated,
yielding 0.220 g of compound (169).
b) Preparation of
##STR00208##
[0459] A mixture of compound (169) (0.0003 mol) and hydrazine
monohydrate (0.1 ml) in ethanol (4 ml) was stirred and refluxed for
1 hour. The reaction mixture was cooled and the solvent was
evaporated. The residue was taken up in DCM and water. The
separated organic layer was dried (MgSO.sub.4), filtered and the
solvent was evaporated. The residue was purified by column
chromatography (eluent: DCM/CH.sub.3OH 90/10). The desired product
fractions were collected and the solvent was evaporated, yielding
0.105 g of compound (139).
c) Preparation of
##STR00209##
[0461] Triethylamine (0.06 ml) was added to a mixture of compound
(139) (0.0002 mol) in DCM (5 ml) at 0.degree. C. Acetyl chloride
(0.0002 mol) was added to the reaction mixture and then stirred for
10 minutes at room temperature. The reaction mixture was washed
with water and then filtered over Isolute. The filtrate's solvent
was evaporated under a N.sub.2 flow. The residue was taken up in
ethyl acetate and in a solution of HCl in diethyl ether. The
precipitate was filtered and dried, yielding 0.032 g of compound
(141).
Example B.39
a) Preparation of
##STR00210##
[0463] Compound (18) (0.0045 mol), tributylethenylstannane (0.0067
mol), tetrakis(triphenyl-phosphine)palladium (0.33 g) and DMF (50
ml) were degassed in a closed vessel. The reaction mixture was
shaken at 80.degree. C. for 24 hours. 1,4-Dioxane (100 ml) and
potassium fluoride (2g) were added . The reaction mixture was
filtered over dicalite. The filtrate was concentrated. The residue
was taken up in DCM and washed with water. The organic layer was
dried (MgSO.sub.4), filtered and evaporated. The residue was
purified by reversed phase HPLC (gradient elution with
NH.sub.4HCO.sub.3 buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN).
The product fractions were collected, evaporated and co-evaporated
with methanol until complete dryness, yielding 0.75 g of compound
(142).
b) Preparation of
##STR00211##
[0465] A mixture of compound (142) (0.0005 mol),
4-methoxybenzenemethanamine (0.014 mol) and
N-ethyl-N-(1-methylethyl)-2-propanamine (0.003 mol) in
N,N-dimethyl-acetamide (5 ml) was stirred for 3 days at 110.degree.
C. After cooling the reaction mixture was taken up in water (20 ml)
and ethyl acetate (50 ml). The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The residue was shaken
overnight with scavenger PS-benzaldehyde (8g) (capacity: 1.2
mmol/g) in DCM (200 ml). The scavenger was removed by filtration.
The filtrate was concentrated and purified on silica gel using
DCM/CH.sub.3OH (7N NH3) (from 100:0 to 96:4) as eluent. The product
fractions were collected and evaporated to dryness. The residue was
used as such in the next reaction, yielding 0.21 g of compound
(157).
c) Preparation of
##STR00212##
[0467] A mixture of compound (157) (0.0003 mol) and
N-ethyl-N-(1-methylethyl)-2-propanamine (0.001 mol) in THF (10 ml)
at room temperature, was added acetic acid 1,1'-anhydride (0.0005
mol). The reaction mixture was shaken in a closed vessel at
35.degree. C. for 1 hour. The reaction mixture was taken up in 100
ml DCM and then washed with 10 ml water. The organic layer was
dried (MgSO.sub.4), filtered and evaporated. The residue was used
as such in the next reaction, yielding 0.2 g of compound (172).
d) Preparation of
##STR00213##
[0469] TFA (10 ml) was added compound (172) (0.0003 mol) in DCM (1
ml) at room temperature. The vessel was closed. The reaction
mixture was shaken for 1 week at 60.degree. C. The reaction mixture
was cooled and the solvent evaporated. The residue was taken up in
DCM and washed with water. The organic layer was dried
(MgSO.sub.4), filtered and evaporated. The residue was purified on
silica gel using DCM/CH.sub.3OH (7N NH.sub.3) (from 100% to 96/4)
as eluent. The product fractions were collected and evaporated to
dryness. The residue was crystallized from DIPE and some
2-propanol. The solid was filtered off, washed and dried, yielding
0.095 g of compound (158).
Example B.40
Preparation of
##STR00214##
[0471] A solution of intermediate (138) (0.3 g, 0.000747 mol) in
chloroform (ethanol free) (10 ml) was cooled to 0.degree. C. mCPBA
(70%) (0.4 g, 3 equiv.) was added and the mixture was stirred for
30 minutes at 0.degree. C., and then for 3 hours at room
temperature. The reaction was quenched with NaOH (1 N) and the
crude product was extracted with chloroform. The separated organic
layer was washed with water and brine, dried (Na.sub.2SO.sub.4) and
the solvent was evaporated to yield 0.286 g of a white foam. The
white foam was purified by reversed phase column chromatography.
The desired product fraction was collected, worked-up and the
solvent was evaporated, yielding 0.097 g of compound (165).
Example B.41
Preparation of
##STR00215##
[0473] A mixture of
2-tert-butyl-5-(2-fluoro-pyridine-4-sulfonyl)-1-[2-(1-oxy-pyrrolidin-1-yl-
)-ethyl]-1H-benzoimidazole (0.0003 mol) in THF (150 ml) was
hydrogenated with palladium on activated carbon (10%) as a
catalyst. After an uptake of hydrogen (3 equiv.) the catalyst was
filtered off and the solvent was evaporated. The residue was
partitioned between DCM (10 ml) and water (1 ml). This mixture was
filtered over Isolute. The filtrate's solvent was evaporated (under
N.sub.2 flow), yielding 0.135 g of residue. 0.100 g of residue was
purified by reversed-phase HPLC (gradient elution with
NH.sub.4HCO.sub.3 buffer (0.25% in water)/CH.sub.3OH/CH.sub.3CN).
The desired product fractions were collected and the solvent was
evaporated. The residue was solidified in DIPE, the precipitate was
filtered off and dried (vacuo, 40.degree. C.), yielding 0.025 g of
compound (144).
[0474] Tables F-1 and F-2 lists the compounds that were prepared by
analogy to one of the above Examples.
TABLE-US-00001 TABLE F-1 ##STR00216## Co. No. 1; Ex. B.1
##STR00217## Co. No. 2; Ex. B.2 ##STR00218## Co. No. 3; Ex. B.2
##STR00219## Co. No. 4; Ex. B.3 ##STR00220## Co. No. 5; Ex. B.1
##STR00221## Co. No. 6; Ex. B.4 ##STR00222## Co. No. 7; Ex. B.4
##STR00223## Co. No. 8; Ex. B.4 ##STR00224## Co. No. 9; Ex. B.4
##STR00225## Co. No. 10; Ex. B.4 ##STR00226## Co. No. 11; Ex. B.4
##STR00227## Co. No. 12; Ex. B.4 ##STR00228## Co. No. 13; Ex. B.4
##STR00229## Co. No. 14; Ex. B.4 ##STR00230## Co. No. 15; Ex. B.4
##STR00231## Co. No. 16, Ex. B.4 ##STR00232## Co. No. 17, Ex. B.4
##STR00233## Co. No. 18; Ex. B.4 ##STR00234## Co. No. 19; Ex. B.5
##STR00235## Co. No. 20; Ex. B.4 ##STR00236## Co. No. 21; Ex. B.4
##STR00237## Co. No. 22; Ex. B.4 ##STR00238## Co. No. 23; Ex. B.4
##STR00239## Co. No. 24; Ex. B.4 ##STR00240## Co. No. 25; Ex. B.4
##STR00241## Co. No. 26; Ex. B.6 ##STR00242## Co. No. 27; Ex. B.4
##STR00243## Co. No. 28; Ex. B.4
TABLE-US-00002 TABLE F-2 ##STR00244## Co. No. 29; Ex. B.4
##STR00245## Co. No. 30; Ex. B.4 ##STR00246## Co. No. 31; Ex. B.2
##STR00247## Co. No. 32; Ex. B.2 ##STR00248## Co. No. 33; Ex. B.2
##STR00249## Co. No. 34; Ex. B.7 ##STR00250## Co. No. 35; Ex. B.4
##STR00251## Co. No. 36; Ex. B.4 ##STR00252## Co. No. 37; Ex. B.8b
##STR00253## Co. No. 38; Ex. B.8b ##STR00254## Co. No. 39; Ex. B.4
##STR00255## Co. No. 40; Ex. B.4 ##STR00256## Co. No. 41; Ex. B.9
##STR00257## Co. No. 42; Ex. B.10a ##STR00258## Co. No. 43; Ex.
B.11 ##STR00259## Co. No. 44; Ex. B.12 ##STR00260## Co. No. 45; Ex.
B.13 ##STR00261## Co. No. 46; Ex. B.8a ##STR00262## Co. No. 47; Ex.
B.14; .cndot.HCl ##STR00263## Co. No. 48; Ex. B.15c ##STR00264##
Co. No. 49; Ex. B.10b ##STR00265## Co. No. 50; Ex. B.4 ##STR00266##
Co. No. 51; Ex. B.4 ##STR00267## Co. No. 52; Ex. B.4 ##STR00268##
Co. No. 53; Ex. B.16 ##STR00269## Co. No. 54; Ex. B.4 ##STR00270##
Co. No. 55; Ex. B.4 ##STR00271## Co. No. 56; Ex. B.4 ##STR00272##
Co. No. 57; Ex. B.4 ##STR00273## Co. No. 58; Ex. B.14; .cndot.HCl
##STR00274## Co. No. 59; Ex. B.4 ##STR00275## Co. No. 60; Ex. B.4
##STR00276## Co. No. 61; Ex. B.3 ##STR00277## Co. No. 62; Ex. B.4
##STR00278## Co. No. 63; Ex. B.14; .cndot.HCl ##STR00279## Co. No.
64; Ex. B.17; .cndot.CH.sub.3SO.sub.2OH ##STR00280## Co. No. 65;
Ex. B.4 ##STR00281## Co. No. 66; Ex. B.4 ##STR00282## Co. No. 67;
Ex. B.4 ##STR00283## Co. No. 68; Ex. B.4 ##STR00284## Co. No. 69;
Ex. B.4 ##STR00285## Co. No. 70; Ex. B.4 ##STR00286## Co. No. 71;
Ex. B.4 ##STR00287## Co. No. 72; Ex. B.4 ##STR00288## Co. No. 73;
Ex. B.4 ##STR00289## Co. No. 74; Ex. B.4; .cndot.HCl ##STR00290##
Co. No. 75; Ex. B.4 ##STR00291## Co. No. 76; Ex. B.4 ##STR00292##
Co. No. 77; Ex. B.18 ##STR00293## Co. No. 78; Ex. B.18 ##STR00294##
Co. No. 79; Ex. B.4 ##STR00295## Co. No. 80; Ex. B.4 ##STR00296##
Co. No. 81; Ex. B.4 ##STR00297## Co. No. 82; Ex. B.4 ##STR00298##
Co. No. 83; Ex. B.4 ##STR00299## Co. No. 84; Ex. B.19 ##STR00300##
Co. No. 85; Ex. B.19 ##STR00301## Co. No. 86; Ex. B.20 ##STR00302##
Co. No. 87; Ex. B.20 ##STR00303## Co. No. 88; Ex. B.20 ##STR00304##
Co. No. 89; Ex. B.21 ##STR00305## Co. No. 90; Ex. B.4 ##STR00306##
Co. No. 91; Ex. B.4 ##STR00307## Co. No. 92; Ex. B.4 ##STR00308##
Co. No. 93; Ex. B.22; .cndot.CH.sub.3SO.sub.2OH ##STR00309## Co.
No. 94; Ex. B.23a ##STR00310## Co. No. 95; Ex. B.24 ##STR00311##
Co. No. 96; Ex. B.21 ##STR00312## Co. No. 97; Ex. B.4 ##STR00313##
Co. No. 98; Ex. B.4 ##STR00314## Co. No. 99; Ex. B.4 ##STR00315##
Co. No. 100; Ex. B.23b ##STR00316## Co. No. 101; Ex. B.25
##STR00317## Co. No. 102; Ex. B.21 ##STR00318## Co. No. 103; Ex.
B.4 ##STR00319## Co. No. 104; Ex. B.4 ##STR00320## Co. No. 105; Ex.
B.4 ##STR00321## Co. No. 106; Ex. B.4 ##STR00322## Co. No. 107; Ex.
B.4 ##STR00323## Co. No. 108; Ex. B.4 ##STR00324## Co. No. 109; Ex.
B.4 ##STR00325## Co. No. 110; Ex. B.4 ##STR00326## Co. No. 111; Ex.
B.4
##STR00327## Co. No. 112; Ex B.4 ##STR00328## Co. No. 113; Ex. B.4
##STR00329## Co. No. 114; Ex. B.4 ##STR00330## Co. No. 115; Ex. B.4
##STR00331## Co. No. 116; Ex. B.30a ##STR00332## Co. No. 117; Ex.
B.30b ##STR00333## Co. No. 118; Ex. B.31 ##STR00334## Co. No. 119;
Ex. B.4 ##STR00335## Co. No. 120; Ex. B.4 ##STR00336## Co. No. 121;
Ex. B.4 ##STR00337## Co. No. 122; Ex. B.32 ##STR00338## Co. No.
123; Ex. B.33a ##STR00339## Co. No. 124; Ex. B.34 ##STR00340## Co.
No. 125, Ex. B.34 ##STR00341## Co. No. 126; Ex. B.33a ##STR00342##
Co. No. 127; Ex. B.4 ##STR00343## Co. No. 128; Ex. B.4 ##STR00344##
Co. No. 129; Ex. B.33d ##STR00345## Co. No. 130; Ex. B.33d
##STR00346## Co. No. 131; Ex. B.33d ##STR00347## Co. No. 132; Ex.
B.33f; .cndot.HCl ##STR00348## Co. No. 133; Ex. B.4 ##STR00349##
Co. No. 134; Ex. B.35b ##STR00350## Co. No. 135; Ex. B.33b;
.cndot.3HCl ##STR00351## Co. No. 136; Ex. B.36;
.cndot.HCl.cndot.H.sub.2O ##STR00352## Co. No. 137; Ex. B.31
##STR00353## Co. No. 138; Ex. B.37;
.cndot.2HCl.cndot.H.sub.2O.cndot.0.5Cl.cndot.0.5H.sub.4N
##STR00354## Co. No. 139, Ex. B.38b ##STR00355## Co. No. 140; Ex.
B.4 ##STR00356## Co. No. 141; Ex. B.38c; 2H.sub.2O.cndot.2HCl
##STR00357## Co. No. 142; Ex. B.39a ##STR00358## Co. No. 143; Ex.
B.21 ##STR00359## Co. No. 144; Ex. B.41 ##STR00360## Co. No. 145;
Ex. B.4 ##STR00361## Co. No. 146; Ex. B.35a, 1,4-TRANS (relative;
mixture) ##STR00362## Co. No. 147; Ex. B.4 ##STR00363## Co. No.
148; Ex. B.4 ##STR00364## Co. No. 149; Ex. B.4 ##STR00365## Co. No.
150; Ex. B.33d ##STR00366## Co. No. 151; Ex. B.33d ##STR00367## Co.
No. 152; Ex. B.33c ##STR00368## Co. No. 153; Ex. B.35c; 1,4-CIS
(relative; mixture) ##STR00369## Co. No. 154; Ex. B.21 ##STR00370##
Co. No. 155; Ex. B.21 ##STR00371## Co. No. 156; Ex. B.28
##STR00372## Co. No. 157; Ex. B.39b ##STR00373## Co. No. 158; Ex.
B.39d ##STR00374## Co. No. 159; Ex. B.26 ##STR00375## Co. No. 160;
Ex. B.4; 1,4-TRANS (relative; mixture) ##STR00376## Co. No. 161;
Ex. B.4 ##STR00377## Co. No. 162; Ex. B.4; 1,4-CIS (relative;
mixture) ##STR00378## Co. No. 163; Ex. B.29 ##STR00379## Co. No.
164; Ex. B.4 ##STR00380## Co. No. 165; Ex. B.40 ##STR00381## Co.
No. 166; Ex. B.4 ##STR00382## Co. No. 167; Ex. B.4 ##STR00383## Co.
No. 168; Ex. B.27 ##STR00384## Co. No. 169; Ex. B.38a ##STR00385##
Co. No. 170; Ex. B.15a ##STR00386## Co. No. 171; Ex. B.15b
##STR00387## Co. No. 172; Ex. B.39c
Compound Identification
LMCS--General Procedure A
[0475] The HPLC measurement was performed using an Alliance HT 2790
(Waters) system comprising a quaternary pump with degasser, an
autosampler, a column oven (set at 40.degree. C., unless otherwise
indicated), a diode-array detector (DAD) and a column as specified
in the respective methods below. Flow from the column was split to
a MS spectrometer. The MS detector was configured with an
electrospray ionization source. Mass spectra were acquired by
scanning from 100 to 1000 in 1 second using a dwell time of 0.1
second. The capillary needle voltage was 3 kV and the source
temperature was maintained at 140.degree. C. Nitrogen was used as
the nebulizer gas. Data acquisition was performed with a
Waters-Micromass MassLynx-Openlynx data system.
LCMS--General Procedure B
[0476] The LC measurement was performed using an Acquity UPLC
(Waters) system comprising a binary pump, a sample organizer, a
column heater (set at 55.degree. C.), a diode-array detector (DAD)
and a column as specified in the respective methods below. Flow
from the column was split to a MS spectrometer. The MS detector was
configured with an electrospray ionization source. Mass spectra
were acquired by scanning from 100 to 1000 in 0.18 seconds using a
dwell time of 0.02 seconds. The capillary needle voltage was 3.5 kV
and the source temperature was maintained at 140.degree. C.
Nitrogen was used as the nebulizer gas. Data acquisition was
performed with a Waters-Micromass MassLynx-Openlynx data
system.
LCMS Method 1
[0477] In addition to general procedure A: Reversed phase HPLC was
carried out on an Xterra MS C18 column (3.5 .mu.m, 4.6.times.100
mm) with a flow rate of 1.6 ml/min. Three mobile phases (mobile
phase A: 95% 25 mM ammoniumacetate+5% acetonitrile; mobile phase B:
acetonitrile; mobile phase C: methanol) were employed to run a
gradient condition from 100% A to 1% A, 49% B and 50% C in 6.5
minutes, to 1% A and 99% B in 1 minute and hold these conditions
for 1 minute and reequilibrate with 100% A for 1.5 minutes. An
injection volume of 10 .mu.l was used. Cone voltage was 10 V for
positive ionization mode and 20 V for negative ionization mode.
LCMS Method 2
[0478] In addition to general procedure A: Reversed phase HPLC was
carried out on an Atlantis C18 column (3.5 .mu.m, 4.6.times.100 mm)
(3.5 .mu.m, 4.6.times.100 mm) with a flow rate of 1.6 ml/min. Two
mobile phases (mobile phase A: 70% methanol+30% H.sub.2O; mobile
phase B: 0.1% formic acid in H.sub.2O/methanol 95/5) were employed
to run a gradient condition from 100% B to 5% B+95% A in 12
minutes. An injection volume of 10 .mu.l was used. Cone voltage was
10 V for positive ionization mode and 20 V for negative ionization
mode.
LCMS Method 3
[0479] In addition to general procedure A: Reversed phase HPLC was
carried out on a Chromolith (4.6.times.25 mm) with a flow rate of 3
ml/min. Three mobile phases (mobile phase A: 95% 25 mM
ammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile;
mobile phase C: methanol) were employed to run a gradient condition
from 96% A, 2% B and 2% C, to 49% B and 49% C in 0.9 minutes, to
100% B in 0.3 minutes and hold for 0.2 minutes. An injection volume
of 2 .mu.l was used. Cone voltage was 10 V for positive ionization
mode and 20 V for negative ionization mode.
LCMS Method 4
[0480] In addition to general procedure A: Column heater was set at
60.degree. C. Reversed phase HPLC was carried out on an Xterra MS
C18 column (3.5 .mu.m, 4.6.times.100 mm) with a flow rate of 1.6
ml/min. Three mobile phases (mobile phase A: 95% 25 mM
ammoniumacetate+5% acetonitrile; mobile phase B: acetonitrile;
mobile phase C: methanol) were employed to run a gradient condition
from 100% A to 50% B and 50% C in 6.5 minutes, to 100% B in 0.5
minute and hold these conditions for 1 minute and reequilibrate
with 100% A for 1.5 minutes. An injection volume of 10 .mu.l was
used. Cone voltage was 10 V for positive ionization mode and 20 V
for negative ionization mode.
LCMS Method 5
[0481] In addition to general procedure B: Reversed phase UPLC
(Ultra Performance Liquid Chromatography) was carried out on a
bridged ethylsiloxane/silica (BEH) C18 column (1.7 .mu.m,
2.1.times.50 mm) with a flow rate of 0.8 ml/min. Two mobile phases
(mobile phase A: 0.1% formic acid in H.sub.2O/methanol 95/5; mobile
phase B: methanol) were used to run a gradient condition from 95% A
and 5% B to 5% A and 95% B in 1.3 minutes and hold for 0.2 minutes.
An injection volume of 0.5 .mu.l was used. Cone voltage was 10 V
for positive ionization mode and 20 V for negative ionization
mode.
LCMS Method 6
[0482] In addition to general procedure A: Reversed phase HPLC was
carried out on a Xbridge C18 column (3.5 .mu.m, 4.6.times.100 mm)
(3.5 .mu.m, 4.6.times.100 mm) with a flow rate of 1.6 ml/min. Two
mobile phases (mobile phase A: 70% methanol+30% H.sub.2O; mobile
phase B: 0.1% formic acid in H.sub.2O/methanol 95/5) were employed
to run a gradient condition from 100% B to 5% B+95% A in 12
minutes. An injection volume of 10 .mu.l was used. Cone voltage was
10 V for positive ionization mode and 20 V for negative ionization
mode.
Melting Points
[0483] For a number of compounds, melting points were determined
with a DSC823e (Mettler-Toledo). In this method, melting points
were measured with a temperature gradient of 30.degree. C./minute.
Maximum temperature was 400.degree. C.
[0484] For a number of compounds melting points were determined
with a Buchi melting point apparatus (in open capillary tubes). The
heating medium was a metal block. The melting of the sample was
visually observed by a magnifying lense and a big light contrast.
Melting points were measured with a temperature gradient of either
3 or 10.degree. C./minute. Maximum temperature was 300.degree.
C.
[0485] For a number of compounds, melting points were obtained with
a Kofler hot bench, consisting of a heated plate with linear
temperature gradient, a sliding pointer and a temperature scale in
degrees Celsius.
[0486] Values are either peak values or melt ranges, and are
obtained with experimental uncertainties that are commonly
associated with this analytical method.
TABLE-US-00003 TABLE F-3 Analytical data - Retention time (R.sub.t
in minutes), (MH).sup.+ peak, LCMS procedure and physico-chemical
data (m.p. is defined as melting point). Co. No. R.sub.t (MH).sup.+
Procedure Physico-chemical data 3 4.51 430 1 -- 4 5.14 456 1 m.p.:
>120.degree. C. (Kofler) 5 5.92 501 1 m.p.: 192-193.degree. C.
(Kofler) 6 5.08 498 1 m.p.: 259.degree. C. (Kofler) 7 1.19 568 5
m.p.: 198.degree. C. (Kofler) 10 6.13 482 1 m.p.: 137.43.degree. C.
(DSC) 11 5.18 445 1 m.p.: 174-180.degree. C. (Kofler) 12 1.01 446 5
m.p.: 234.8.degree. C. (DSC) 13 5.26 428 1 m.p.: 180.1.degree. C.
(DSC) 14 5.47 480 4 -- 15 1.19 432 5 -- 16 4.87 457 1 m.p.:
247.1.degree. C. (DSC) 17 5.51 439 1 m.p.: 201.2.degree. C. (DSC)
18 5.77 448 1 m.p.: 201.0.degree. C. (DSC) 19 4.85 429 1 m.p.:
235.9.degree. C. (DSC) 20 1.05 481 5 m.p.: 165.2.degree. C. (DSC)
21 5.24 498 1 m.p.: 205.8.degree. C. (DSC) 22 4.56 471 4 m.p.:
262.3.degree. C. (DSC) 23 5.79 512 4 m.p.: 166.7.degree. C. (DSC)
24 1.19 442 5 m.p.: 207.1.degree. C. (DSC) 26 6.29 429 1 HCl-salt
27 4.90 490 1 m.p.: 200.degree. C. (Kofler) 28 4.70 444 1 m.p.:
170.degree. C. (Kofler) 29 0.75 458 3 m.p.: 220-222.degree. C.
(Kofler) 30 0.87 472 3 m.p.: 195-197.degree. C. (Kofler) 31 5.09
433 1 32 4.95 440 1 33 4.59 457 1 34 0.81 430 3 35 6.68 470 1 36
1.27 437 3 m.p.: 215-216.degree. C. (Kofler) 37 6.33 513 1 m.p.:
206-207.degree. C. (Kofler) 38 6.42 509 1 39 6.12 428 1 40 1.15 461
5 m.p.: 151.degree. C. (Kofler) 41 1.08 463 5 m.p.: 192.degree. C.
(Kofler) 42 4.79 458 1 m.p.: 177-179.degree. C. (Kofler) 43 5.33
439 1 m.p.: 240.degree. C. (Kofler) 44 4.63 457 1 m.p.: 259.degree.
C. (Kofler) 45 5.47 500 1 m.p.: 191.degree. C. (Kofler) 46 5.57 456
1 47 5.11 498 1 m.p.: 255-260.degree. C. (Kofler) HCl-salt 48 5.74
487 1 m.p.: 199.degree. C. (Kofler) 49 5.35 472 1 m.p.: 140.degree.
C. (Kofler) 50 5.59 456 1 m.p.: 162.degree. C. (Kofler) 51 5.43 439
1 m.p.: 228.degree. C. (Kofler) 52 5.66 444 1 m.p.: 198.degree. C.
(Kofler) 53 5.35 477 1 m.p.: 258.degree. C. (Kofler) 55 5.35 475 1
m.p.: 141.0.degree. C. (Kofler) 56 1.05 492 5 m.p.: 150-160.degree.
C. (Kofler) 57 1.09 497 5 m.p.: 216.degree. C. (Kofler) 58 4.79 497
4 m.p.: 224.0.degree. C. (DSC) HCl-salt 59 1.15 526 5 m.p.:
158.degree. C. (Kofler) 60 1.17 428 5 m.p.: 145.5-145.7.degree. C.
(Buchi) 61 6.03 516 1 62 1.17 575 5 m.p.: 200.degree. C. (Kofler)
63 see compound 62 (free base) m.p.: 219.36.degree. C. (DSC)
HCl-salt 64 see compound 62 (free base) m.p.: 216.3.degree. C.
(DSC) methanesulfonate-salt 65 1.26 646 5 m.p.: 230.degree. C.
(Kofler) 66 1.11 563 5 m.p.: 224.degree. C. (Kofler) 67 1.01 492 5
m.p.: 183.degree. C. (Kofler) 68 5.35 495 1 m.p.: 204-205.degree.
C. (Kofler) 69 4.73 444 1 m.p.: 216.degree. C. (Kofler) 70 5.79 444
1 71 5.53 482 4 m.p.: 198.degree. C. (Kofler) 72 1.28 462 5 m.p.:
139.6-140.2.degree. C. (Buchi) 73 1.02 462 5 m.p.: 209.4.degree. C.
(DSC) 74 1.14 500 5 m.p.: 108.5.degree. C. (DSC) HCl-salt 75 1.04
460 5 m.p.: 231.degree. C. (Kofler) 76 5.31 570 1 77 4.91 507 1 78
5.29 522 1 79 1.08 532 5 m.p.: 184.6.degree. C. (DSC) 80 5.15 516 1
m.p.: 172.1.degree. C. (DSC) 81 1.26 491 5 m.p.: 185.8.degree. C.
(DSC) 82 1.04 448 5 m.p.: 291.8-294.6.degree. C. (Buchi) 83 4.89
480 4 84 5.98 482 1 m.p.: 242.9.degree. C. (DSC) 85 5.65 466 1
m.p.: 192.9.degree. C. (DSC) 86 4.40 492 1 87 4.89 508 1 m.p.:
205.3.degree. C. (DSC) 88 5.20 476 1 m.p.: 184.7.degree. C. (DSC)
89 4.72 444 1 m.p.: 215.3.degree. C. (DSC) 90 5.64 600 1 m.p.:
113.9.degree. C. (DSC) 91 5.44 600 1 m.p.: 164.4.degree. C. (DSC)
92 1.02 456 5 m.p.: 161.1.degree. C. (DSC) 93 5.49 439 1 m.p.:
215.7.degree. C. (DSC) methanesulfonate-salt 94 0.98 431 5 m.p.:
218.3.degree. C. (DSC) 95 4.87 482 1 96 4.39 487 4 m.p.:
247.2.degree. C. (DSC) 98 1.07 439 5 m.p.: 224.5-226.7.degree. C.
(Buchi) 99 1.23 482 5 m.p.: 140.5-142.3.degree. C. (Buchi) 100 4.89
445 1 m.p.: 224.3.degree. C. (DSC) 101 4.88 472 1 m.p.:
290.1.degree. C. (DSC) 102 4.67 458 4 m.p.: 231.7.degree. C. (DSC)
103 4.91 444 1 m.p.: 259.7.degree. C. (DSC) 104 1.03 439 5 m.p.:
100.0-105.0.degree. C. (Buchi) 105 1.23 482 5 m.p.:
139.5-141.0.degree. C. (Buchi) 106 1.29 471 5 m.p.:
168.0-169.5.degree. C. (Buchi) 107 5.06 429 1 m.p.: 179.7.degree.
C. (DSC) 108 1.30 512 5 110 1.19 482 5 m.p.: decomposition at
190.degree. C. (Buchi) 111 1.13 445 5 m.p.: decomposition at
170.degree. C. (Buchi) 112 5.06 459 1 m.p.: 196.7.degree. C. (DSC)
113 5.74 446 4 m.p.: 179.8.degree. C. (DSC) 114 5.17 473 1 m.p.:
193.9.degree. C. (DSC) 115 4.07 460 4 116 3.87 443 4 117 4.61 485 1
m.p.: 199.4.degree. C. (DSC) 118 0.99 417 5 119 1.28 482 5 120 6.79
418 1 m.p.: 131.5.degree. C. (DSC) 121 5.04 515 1 m.p.:
182.3.degree. C. (DSC) 122 5.65 478 4 123 4.24 514 4 m.p.:
217.2.degree. C. (DSC) 124 5.43 474 1 125 5.94 474 1 126 4.83 501 4
m.p.: 148.3.degree. C. (DSC) 127 5.58 404 4 m.p.: 135.4.degree. C.
(DSC) 128 5.09 446 4 m.p.: 177.8.degree. C. (DSC) 129 4.67 515 1
m.p.: 119.4.degree. C. (DSC) 131 4.46 487 1 132 6.53 529 6 HCl-salt
133 5.77 480 6 m.p.: 220.8.degree. C. (DSC) 134 1.18 444 5 m.p.:
164.8.degree. C. (DSC) 136 8.02 402 6 HCl-salt m.p.: 184.3.degree.
C. (DSC) 137 0.99 417 5 138 5.73 499 4
.cndot.2HCl.cndot.H.sub.2O.cndot.0.5Cl.cndot.0.5H.sub.4N 139 4.36
485 1 140 5.95 444 1 m.p.: 138.9.degree. C. (DSC) 141 6.31 527 6
HCl-salt 142 7.03 440 6 143 4.97 471 6 144 5.76 431 1 m.p.:
115.5.degree. C. (DSC) 145 5.13 460 1 146 7.17 446 2 m.p.:
163.6.degree. C. (DSC) 147 6.68 418 1 m.p.: 130.9.degree. C. (DSC)
148 1.41 418 5 149 5.70 460 4 m.p.: 159.4.degree. C. (DSC) 150 7.08
488 6 m.p.: 142.9.degree. C. (DSC) 151 7.51 502 6 m.p.:
106.5.degree. C. (DSC) 152 6.62 488 6 m.p.: 161.5.degree. C. (DSC)
154 6.89 486 6 m.p.: 143.4.degree. C. (DSC) 155 6.32 502 6 156 4.74
444 6 m.p.: 213.9.degree. C. (DSC) 157 5.16 577 1 158 4.60 499 1
m.p.: 160.3.degree. C. (DSC) 159 6.74 485 2 m.p.: 181.2.degree. C.
(DSC) 160 5.91 460 1 161 1.08 475 5 162 6.14 460 1 m.p.:
133.5.degree. C. (DSC) 163 5.15 442 1 m.p.: 201.5.degree. C. (DSC)
164 5.97 457 1 m.p.: 122.0.degree. C. (DSC) 165 1.20 434 5 166 5.16
442 1 m.p.: 277.5.degree. C. (DSC) 167 6.41 470 1 m.p.:
137.7.degree. C. (DSC) 168 5.95 458 2 m.p.: 166.2.degree. C. (DSC)
170 1.02 444 3 m.p.: 156.0.degree. C. (Kofler) 171 4.86 477 1 172
5.73 619 1
TABLE-US-00004 TABLE F-4 Analytical data - Retention time (R.sub.t
in minutes), (MH).sup.- peak, LCMS procedure and physico-chemical
data (m.p. is defined as melting point). Co. No. R.sub.t (MH).sup.-
Procedure Physico-chemical data 1 0.83 428 3 2 0.74 412 3 8 4.10
428 4 m.p.: >300.degree. C. (Kofler) 97 4.89 510 4 m.p.:
152.9.degree. C. (DSC) 9 6.16 456 1 m.p.: 174.degree. C. (Kofler)
25 5.05 430 4 m.p.: 171.3.degree. C. (DSC)
C. Pharmacological Examples
[0487] C.1 Inhibition of cAMP in Response to Activation of the
Human CB1 and CB2 Receptors
[0488] Functional activity of the test compounds was assessed by
measuring their potency to inhibit forskolin-activated cAMP
production upon activation of the human CB1 (hCB1) or human CB2
(hCB2) receptor through homogenous time resolved fluorescence
(HTRF) assays.
[0489] CHO--K1 cells stably transfected with either hCB1 or hCB2
were grown up to 80-90% confluence in T175 Falcon flasks in
DMEM/NUT MIX F-12 culture medium complemented with 2% Solution A
(5.10.sup.6 IU/l penicillin G, 5g/l streptomycin sulphate, 5.5 g/l
pyruvate, 14.6 g/l L-glutamine, 1M NaOH) and 10% foetal calf serum.
Before the experiments, medium was removed, cells were washed with
PBS/EDTA (140 mM NaCl, 1 mM Na.sub.2-EDTA, 8 mM
Na.sub.2HPO.sub.4.2H.sub.2O, 8.5 mM KH.sub.2PO.sub.4, 2.7 mM KCl,
21 mM glucose), resuspended in stimulation buffer (HBSS 1.times.,
IBMX 1 mM, Hepes 5 mM, MgCl2 10 mM, BSA 0.1%, pH 7.4). Cells were
diluted to a concentration of 8.10.sup.5 cell/ml for hCB1
experiments and 10.sup.6 cells/ml for hCB2 experiments. Assays were
performed using the cAMP Dynamic HTRF kit (CIS bio international,
France) according to the recommendations of the manufacturer.
[0490] For CB1, each well of a 96 flat bottom black polystyrene
assay plate (Costar) was filled with 25 .mu.l stimulation buffer
containing 6 .mu.M forskolin and either test compound (in 2% DMSO),
2% DMSO or 2 .mu.M CP55490 (in 2% DMSO). Then, 25 .mu.l of the
diluted cells was added (20,000 cells/well). After 30 minutes
incubation in dark at room temperature, 25 .mu.l cAMP-XL665 and 25
.mu.l anti-cAMP cryptate (both at a final dilution of 1/80) was
added to the cells.
[0491] For CB2, each well of a 384 flat bottom black polystyrene
assay plate (Costar) was filled with 10 .mu.l stimulation buffer
containing 15 .mu.M forskolin and either test compound (in 3%
DMSO), 3% DMSO or 10 .mu.M Win55212-2 (in 3% DMSO). Then, 20 .mu.l
of the diluted hCB2-CHO--K1 cells was added (20,000 cells/well).
After 30 minutes incubation in dark at room temperature, 10 .mu.l
cAMP-XL665 and 10 .mu.l anti-cAMP cryptate (both at a final
dilution of 1/100) was added to the cells.
[0492] After equilibration of the reaction mixtures for 1 to 24
hours in dark at room temperature, fluorescence was measured at 665
nm and 620 nm using a Discovery microplate fluorescence counter
(Perkin Elmer), and the signal. ratio of 665 nm /620 nm was
calculated. The signal ratios of the test compounds were expressed
relative to the signal ratios of the DMSO control (maximal signal
ratio, no inhibition of cAMP) and CP55490 or WIN55212-2 for hCB1.
and hCB2, respectively (minimal signal ratio, maximal inhibition of
cAMP). From the dose response curves generated for each test
compound, the dose at which 50% of the maximal inhibition of cAMP
level is observed (EC.sub.50, expressed in the Tables as
pEC.sub.50=-log(EC.sub.50) values) and the level of inhibition
reached with 10 .mu.M of the test compound compared to CP55490 (for
hCB1) or WIN55212-2 (for hCB2) was calculated.
TABLE-US-00005 TABLE C-1 pEC50 values for CB-1 and CB-2 agonism
ratio CB2 agonism Co. No. CB2 pEC50 CB1 pEC50 over CB1 agonism 1
8.30 <5 >1995 2 7.42 <5 >263 3 8.76 6.16 398 4 8.72
5.49 1679 5 9.43 6.59 676 7 8.74 <5 >5495 8 8.51 5.33 1514 9
9.48 5.85 4266 10 9.13 5.02 12883 11 8.90 7.22 48 12 8.81 6.33 302
13 8.90 5.69 1622 14 9.11 5.42 4898 15 8.98 6.24 556 16 8.63 6.07
359 17 8.80 5.03 5821 18 9.17 6.20 933 19 8.95 6.14 638 20 8.90
6.36 347 21 8.42 5.00 2630 22 8.95 5.70 1758 23 8.99 6.39 398 24
8.66 6.05 407 25 9.09 6.39 495 26 9.10 6.27 676 27 9.15 <5
>14125 28 8.54 <5 >3467 29 8.50 5.88 417 30 8.77 5.28 3055
31 8.92 6.37 353 32 8.59 5.12 2951 33 8.51 5.24 1884 34 8.80 5.13
4732 35 9.39 7.49 79 36 9.17 7.14 108 37 9.03 <5.00 >10839 38
8.56 <5.00 >3631 39 8.77 5.69 1216 40 8.97 6.68 193 42 9.20
6.97 168 42 8.40 <5.00 >2512 43 9.00 5.79 1622 44 8.70 6.90
64 45 8.52 <5.00 >3311 46 8.98 5.41 3758 47 8.77 5.83 871 48
9.24 6.70 347 49 8.33 <5.00 >2138 50 9.16 5.35 6457 51 8.91
7.05 73 52 9.16 6.64 331 53 8.43 5.65 607 54 9.03 6.91 133 55 8.64
6.08 363 56 8.58 <5.00 >3802 57 8.96 5.84 1328 58 9.08 5.74
2188 59 8.95 5.64 2018 60 8.98 6.18 638 61 8.95 6.82 135 62 9.23
5.71 3299 63 9.01 5.55 2818 64 9.32 5.73 3920 65 8.53 <5.00
>3388 66 7.83 <5.00 >676 67 8.37 <5.00 >2344 68 8.51
6.44 116 69 8.76 6.16 398 70 9.26 5.85 2570 71 9.13 <5.00
>13490 72 9.17 5.99 1525 73 8.86 6.93 84 74 8.50 5.68 668 75
8.38 5.02 2291 76 7.92 <5.00 >832 77 8.71 5.59 1303 78 8.14
<5.00 >1380 79 8.53 5.80 543 80 8.38 4.98 2483 81 9.30 5.97
2138 82 8.41 5.80 407 83 8.70 6.39 209 84 8.90 6.21 490 85 9.03
6.08 891 86 7.92 <5.00 >832 87 8.67 5.64 1072 88 8.63 5.90
537 89 7.95 <5.00 >891 90 8.57 <5.00 >3715 91 8.30 5.00
1995 92 8.16 5.53 437 93 8.83 <5.00 >6761 94 8.60 5.57 1059
95 8.24 <5.00 >1738 96 8.70 <5.00 >5012 97 8.73 5.41
2065 98 9.02 6.13 794 99 8.88 6.03 700 100 8.80 6.00 631 101 8.60
6.83 58 102 8.30 5.04 1820 103 8.15 5.68 295 104 9.13 7.06 117 105
8.80 6.32 295 106 9.14 6.50 432 107 8.62 5.81 646 108 8.59 <5.00
>3890 109 9.09 6.58 324 110 9.26 5.98 1905 111 8.94 6.37 372 112
8.31 <5.00 >2030 113 8.58 6.10 302 115 8.43 5.44 977 116 8.23
5.24 966 117 8.35 6.01 219 118 8.75 6.11 437 119 8.15 <5.00
>1413 120 8.64 <5.00 >4365 121 8.51 5.55 912 122 9.01 7.00
102 123 8.38 <5.00 >2399 124 7.84 <5.00 >692 125 8.60
<5.00 >3981 126 9.07 6.02 1129 127 8.78 <5.00 6026 128
8.68 <5.00 >4786 129 7.81 5.02 617 130 8.64 <5.00 >4315
131 7.80 <5.00 >631 132 8.85 <5.00 >7079 133 8.40
<5.00 >2512 134 8.86 5.42 2786 135 8.66 <5.00 >4571 136
9.36 <5.00 >22734 137 8.95 6.11 687 138 8.76 6.08 473 139
7.88 <5.00 >759 141 8.25 <5.00 >1792 142 9.02 5.87 1413
143 7.77 <5.00 >589 144 8.49 <5.00 >3090 145 8.49
<5.00 >3090 146 8.60 <5.00 >3981 147 9.02 <5.00
>10471 148 9.59 <5.00 >38905 149 8.90 <5.00 >8035
150 8.90 6.09 638 151 9.32 5.41 8035 152 8.93 5.44 3090 153 9.07
<5.00 >11749 154 8.95 <5.00 >9016 155 8.60 <5.00
>3951 156 8.39 5.60 617 157 8.46 <5.00 >2884 158 8.85 5.08
5888 159 8.67 <5.00 >4677 160 8.37 <5.00 >2344 161 8.74
5.28 2951 162 9.44 <5.00 >27542 165 7.97 <5.00 >923 168
8.09 <5.00 >1230
C.2 Compative data
[0493] Table C.2 lists a number of sulfonyl benzimidazole
derivatives bearing an unsubstituted heterocyclic moiety on the
sulfonyl group. These compounds are covered by reference
WO-2006/048754.
TABLE-US-00006 TABLE C-2 ##STR00388## Co. No. A ##STR00389## Co.
No. B ##STR00390## Co. No. C ##STR00391## Co. No. D ##STR00392##
Co. No. E
[0494] The ratio of CB2 agonism over CB1 agonism of the compounds A
to E was measured using the same procedures as described in
Pharmacological Example C.1. Table C-3 lists the ratio of CB2 over
CB1 in comparison with the ratio of CB2 over CB1 for the compounds
of formula (I) that structurally differ by the presence of a
substituent on the heterocyclic moiety on the sulfonyl group.
TABLE-US-00007 TABLE C-3 comparison between art compounds A to E
and compounds of the present invention ratio CB2 over ratio CB2
over Co. No. CB1 agonism Co. No. CB1 agonism A 215 3 398 215 8 1514
215 9 4266 215 14 4898 215 17 5821 215 19 638 215 21 2630 215 22
1758 215 23 398 215 25 495 B 30 1 1995 30 28 3467 C 36 4 1679 36 10
12883 D 26 12 302 26 20 346 E 219 24 407
[0495] The compounds of the present invention are more selective
CB2 agonists than the art compounds A to E.
* * * * *